rs193919340

Positions:

• chr2-73490120-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001378454.1(ALMS1):​c.8161C>T​(p.Arg2721Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R2721R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 0.493

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-73490120-C-T is Pathogenic according to our data. Variant chr2-73490120-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.8161C>T	p.Arg2721Ter	stop_gained	10/23	ENST00000613296.6
ALMS1	NM_015120.4	c.8164C>T	p.Arg2722Ter	stop_gained	10/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.8161C>T	p.Arg2721Ter	stop_gained	10/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249546 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135396

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000365 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alstrom syndrome Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 18, 2022	- -
Uncertain significance, flagged submission	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 13, 2023	This sequence change creates a premature translational stop signal (p.Arg2722*) in the ALMS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALMS1 are known to be pathogenic (PMID: 17594715). This variant is present in population databases (rs193919340, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Alstrom syndrome (PMID: 17850632). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3975). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2007	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 18, 2023

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34426522, 17850632, 25864795, Gosadi2021[paper], BeaMascato2022[preprint], 26283575, 33981653, 33969109, 33101984, 17594715, 25296579, 22688943, Wicher2017[paper]) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.53	D
MutationTaster	Benign	1.0	A;A
Vest4		0.84
GERP RS		2.3

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: rs193919340; hg19: chr2-73717247;