rs201252809

chr2-73490370-G-Achr2-73490370-G-Cchr2-73490370-G-T

Variant summary

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

The NM_001378454.1(ALMS1):c.8411G>A(p.Arg2804His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000477 in 1,613,338 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 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. R2804C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (2 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:3
• Conservation: PhyloP100: 0.838

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=0.009348363).
• BP6: Variant 2-73490370-G-A is Benign according to our data. Variant chr2-73490370-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 393018.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=6}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000506 (77/152286) while in subpopulation NFE AF= 0.000912 (62/68010). AF 95% confidence interval is 0.000729. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.8411G>A	p.Arg2804His	missense_variant	10/23	ENST00000613296.6
ALMS1	NM_015120.4	c.8414G>A	p.Arg2805His	missense_variant	10/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.8411G>A	p.Arg2804His	missense_variant	10/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000912

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000487 AC: 121 AN: 248568 Hom.: 1 AF XY: 0.000497 AC XY: 67 AN XY: 134930

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.000326

Gnomad NFE exome AF: 0.000877

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000474 AC: 692 AN: 1461052 Hom.: 2 Cov.: 32 AF XY: 0.000482 AC XY: 350 AN XY: 726744

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.000359

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.000571

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74466

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000912

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000619 Hom.: 0

Bravo AF: 0.000514

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000828 AC: 3

ESP6500EA AF: 0.000860 AC: 7

ExAC AF: 0.000513 AC: 62

EpiCase AF: 0.000491

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Alstrom syndrome Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Oct 08, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ALMS1: PM2, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 05, 2017	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Aug 16, 2016	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 14, 2023

Variant summary: ALMS1 c.8408G>A (p.Arg2803His) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 248568 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy (0.00049 vs 0.0018), allowing no conclusion about variant significance. c.8408G>A has been reported in the literature in at least one individual affected with Alstrom Syndrome. This report does not provide unequivocal conclusions about association of the variant with Alstrom Syndrome With Dilated Cardiomyopathy. our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25846608). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (likely benign n=3, VUS n=6). 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

Aug 22, 2022

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	0.049
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	13
Dann	Benign	0.59
DEOGEN2	Benign	0.0064	T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.52	T;T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.0093	T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
Sift4G	Benign	1.0	T;T;T
Vest4		0.092
MVP		0.072
ClinPred		0.0063	T
GERP RS		3.4
Varity_R		0.041
gMVP		0.035

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: rs201252809; hg19: chr2-73717497;