rs200266868

chr2-73451989-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_001378454.1(ALMS1):c.5462C>T(p.Pro1821Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,613,398 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1821P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00063 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 1.66

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.00670892).
• BP6: Variant 2-73451989-C-T is Benign according to our data. Variant chr2-73451989-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241003.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000626 (95/151792) while in subpopulation AMR AF= 0.00321 (49/15274). AF 95% confidence interval is 0.00249. There are 1 homozygotes in gnomad4. There are 50 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.5462C>T	p.Pro1821Leu	missense_variant	8/23	ENST00000613296.6
ALMS1	NM_015120.4	c.5465C>T	p.Pro1822Leu	missense_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.5462C>T	p.Pro1821Leu	missense_variant	8/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.000626 AC: 95 AN: 151672 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000993

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000149 AC: 37 AN: 248964 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135148

Gnomad AFR exome AF: 0.000971

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000887

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000114 AC: 166 AN: 1461606 Hom.: 0 Cov.: 38 AF XY: 0.0000921 AC XY: 67 AN XY: 727104

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000702

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000626 AC: 95 AN: 151792 Hom.: 1 Cov.: 32 AF XY: 0.000674 AC XY: 50 AN XY: 74212

Gnomad4 AFR AF: 0.000990

Gnomad4 AMR AF: 0.00321

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0000956 Hom.: 0

Bravo AF: 0.000816

ESP6500AA AF: 0.000814 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000157 AC: 19

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Alstrom syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Apr 22, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1822 of the ALMS1 protein (p.Pro1822Leu). This variant is present in population databases (rs200266868, gnomAD 0.09%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with Alstrom syndrome (PMID: 22876109). ClinVar contains an entry for this variant (Variation ID: 241003). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2022	Observed heterozygous with no other ALMS1 variant in a patient with Alstrom syndrome in published literature (Pieiro-Gallego T et al., 2012); Observed in a patient with a diagnosis of blindness in published literature, although additional clinical information was not provided (Dieiro et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22876109, 32483926) -

Monogenic diabetes Benign:1

Likely benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

May 19, 2017

ACMG criteria: PP3 (4 predictors), BP4 (5 predictors), BP1 (missense when truncating is disease causing)=likely benign -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 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	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0067	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
Sift4G	Uncertain	0.0030	D;D;D
Vest4		0.21
MVP		0.39
ClinPred		0.029	T
GERP RS		3.3
Varity_R		0.048
gMVP		0.22

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: rs200266868; hg19: chr2-73679116;