rs201390755

chr2-73451716-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001378454.1(ALMS1):c.5189A>G(p.Glu1730Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000784 in 1,613,844 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (2 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: -0.239

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004495442).
• BP6: Variant 2-73451716-A-G is Benign according to our data. Variant chr2-73451716-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241001.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=5}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000697 (106/152016) while in subpopulation NFE AF= 0.00104 (71/67982). AF 95% confidence interval is 0.000848. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.5189A>G	p.Glu1730Gly	missense_variant	8/23	ENST00000613296.6
ALMS1	NM_015120.4	c.5192A>G	p.Glu1731Gly	missense_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.5189A>G	p.Glu1730Gly	missense_variant	8/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.000698 AC: 106 AN: 151896 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000851 AC: 212 AN: 249014 Hom.: 0 AF XY: 0.000955 AC XY: 129 AN XY: 135076

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00438

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000980

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.000793 AC: 1159 AN: 1461828 Hom.: 2 Cov.: 39 AF XY: 0.000832 AC XY: 605 AN XY: 727218

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00425

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.000777

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000697 AC: 106 AN: 152016 Hom.: 0 Cov.: 32 AF XY: 0.000659 AC XY: 49 AN XY: 74302

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000832

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00107 Hom.: 1

Bravo AF: 0.000642

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00146 AC: 12

ExAC AF: 0.000861 AC: 104

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Alstrom syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Apr 06, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 12, 2023	Variant summary: ALMS1 c.5186A>G/p.Glu1729Gly (also known as c.5192A>G in RefSeq) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00085 in 249014 control chromosomes, predominantly at a frequency of 0.001 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy (0.00085 vs 0.0018), allowing no conclusion about variant significance. c.5186A>G has been reported in two heterozygous individuals with clinical features of Alstrom Syndrome without strong evidence for causality (Marshall_2015). This report does not provide unequivocal conclusions about association of the variant with Alstrom Syndrome With Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25846608, 26283575). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=2) or likely benign (n=5). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 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	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	7.5
Dann	Benign	0.87
DEOGEN2	Benign	0.030	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.29	T;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.0045	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.22	T
Sift4G	Benign	0.15	T;T;T
Vest4		0.094
MVP		0.12
ClinPred		0.0071	T
GERP RS		-0.94
Varity_R		0.053
gMVP		0.063

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: rs201390755; hg19: chr2-73678843;