rs183407241

Variant names:

• chr2-73385928-G-A
• rs183407241
• NM_001378454.1:c.60G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-73385928-G-A
• chr2-73385928-G-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_001378454.1(ALMS1):​c.60G>A​(p.Glu20Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000557 in 898,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.443
• Publications: 1 publications found

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]

ALMS1 Gene-Disease associations (from GenCC):

• Alstrom syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Orphanet, Genomics England PanelApp

ENSG00000285068 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-73385928-G-A is Benign according to our data. Variant chr2-73385928-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 412662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.443 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.60G>A	p.Glu20Glu	synonymous_variant	Exon 1 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.60G>A	p.Glu20Glu	synonymous_variant	Exon 1 of 23		NP_055935.4
LOC105374804	XR_007087045.1	n.-247C>T		upstream_gene_variant
LOC105374804	XR_007087053.1	n.-247C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.60G>A	p.Glu20Glu	synonymous_variant	Exon 1 of 23	1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000513 AC: 7 AN: 136516 AF XY: 0.0000552

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000835

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000590

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.00000557 AC: 5 AN: 898338 Hom.: 0 Cov.: 12 AF XY: 0.00000650 AC XY: 3 AN XY: 461650

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21134

American (AMR) AF: 0.0000290 AC: 1 AN: 34534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21462

East Asian (EAS) AF: 0.00 AC: 0 AN: 33346

South Asian (SAS) AF: 0.00 AC: 0 AN: 67402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3800

European-Non Finnish (NFE) AF: 0.00000636 AC: 4 AN: 628808

Other (OTH) AF: 0.00 AC: 0 AN: 41568

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.018479), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.000503 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ALMS1: BP4, BP7 -

Jun 21, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Apr 15, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jul 18, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Alstrom syndrome Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.5
DANN	Benign	0.87
PhyloP100		0.44
PromoterAI		0.18	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs183407241; hg19: chr2-73613056;