2-73519947-C-T

Position:

• chr2-73519947-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The ENST00000613296.6(ALMS1):​c.9712C>T​(p.Arg3238Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000415 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3238H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: ALMS1 ENST00000613296.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.953

Genes affected

ALMS1 (HGNC:428): (ALMS1 centrosome and basal body associated protein) This gene encodes a protein containing a large tandem-repeat domain as well as additional low complexity regions. The encoded protein functions in microtubule organization, particularly in the formation and maintanance of cilia. Mutations in this gene cause Alstrom syndrome. There is a pseudogene for this gene located adjacent in the same region of chromosome 2. Alternative splice variants have been described but their full length nature has not been determined. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011186659).
• BP6: Variant 2-73519947-C-T is Benign according to our data. Variant chr2-73519947-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 403927.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.9712C>T	p.Arg3238Cys	missense_variant	11/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.9715C>T	p.Arg3239Cys	missense_variant	11/23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.9712C>T	p.Arg3238Cys	missense_variant	11/23	1	NM_001378454.1	ENSP00000482968	P3

Frequencies

GnomAD3 genomes AF: 0.000500 AC: 76 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000589 AC: 147 AN: 249464 Hom.: 0 AF XY: 0.000569 AC XY: 77 AN XY: 135344

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00695

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.000557

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.000406 AC: 593 AN: 1461778 Hom.: 0 Cov.: 32 AF XY: 0.000432 AC XY: 314 AN XY: 727188

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00540

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.000358

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.000500 AC: 76 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00779

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000965 Hom.: 3

Bravo AF: 0.000502

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000486 AC: 4

ExAC AF: 0.000546 AC: 66

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2020	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	May 02, 2017	p.Arg3239Cys (c.9715C>T) in exon 11 of the ALMS1 gene (NM_015120.4) Chromosome position: 2:73747074 C / T Based on the information reviewed below, including this variant’s relatively high frequency in the Ashkenazi Jewish population (MAF=0.73%), coupled with poor conservation at this residue across evolution (several species have Cysteine as the default amino acid), we classify it as a Variant of Uncertain Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. The ALMS1 gene is associated with autosomal recessive Alstrom syndrome (MedGen UID: 78675). For this reason, any one heterozygous variant is an unlikely explanation for disease, although it cannot be ruled out. This variant has not been reported in the literature in association with disease. It has been reported to ClinVar only by Invitae as of 4/29/2017. This is a non-conservative amino acid change, resulting in the replacement of a positively-charged Arginine with a polar Cysteine that it capable of forming disulfide bridges. Arginine at this location is very poorly conserved across vertebrate species. In fact, Cysteine is the default amino acid in at least 3 species. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). There are no Likely Pathogenic or Pathogenic variants listed within 10 amino acids of this residue in ClinVar as of 4/29/2017. Most Pathogenic variants in ALMS1 listed in ClinVar are truncating (frameshift or nonsense) and not missense like this one. This particular transcript for ALMS1 is not found in gnomAD. However, there is an Arg3237Cys variant in gnomAD (rs201252375) that appears to be the same thing. It has been reported in 170 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Overall MAF: 0.06%. Specifically, the variant was observed in 74/5,075 Ashkenazi Jews (for the highest allele frequency: 0.73%), 81/63,302 non-Finnish Europeans, 6 Finnish Europeans, 6 Other, 2 Latinos, and 1 South Asian. Our patient’s ancestry is from Belarus and Ukraine. The phenotype of the individuals in gnomAD is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ALMS1: BP4 -

Alstrom syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 05, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 09, 2020

Variant summary: ALMS1 c.9709C>T (p.Arg3237Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00059 in 249464 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Alstrom Syndrome (0.00059 vs 0.0014), allowing no conclusion about variant significance. c.9709C>T has been reported in the literature in individuals affected with Alstrom Syndrome or Very Early Onset Atrial Fibrillation (Zmyslowska_2016, Goodyer_2019). These reports do not provide unequivocal conclusions about association of the variant with Alstrom Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T;.;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.57	T;T;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.20	T
Sift4G	Benign	0.088	T;T;T
Vest4		0.26
MVP		0.11
ClinPred		0.14	T
GERP RS		-5.4
Varity_R		0.049
gMVP		0.068

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201252375; hg19: chr2-73747074;