rs769291842

Variant names:

• chr2-73448747-T-TA
• rs769291842
• NM_001378454.1:c.2221dupA

Your query was ambiguous. Multiple possible variants found:

• chr2-73448747-T-TA
• chr2-73448747-T-TAG
• chr2-73448747-T-TATA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001378454.1(ALMS1):​c.2221dupA​(p.Thr741AsnfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000688 in 1,453,110 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T741T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.0850
• Publications: 0 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

ENSG00000295621 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 2-73448747-T-TA is Pathogenic according to our data. Variant chr2-73448747-T-TA is described in ClinVar as Pathogenic. ClinVar VariationId is 552645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378454.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	NM_001378454.1	MANE Select	c.2221dupA	p.Thr741AsnfsTer2	frameshift	Exon 8 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.2221dupA	p.Thr741AsnfsTer2	frameshift	Exon 8 of 23	NP_055935.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.2221dupA	p.Thr741AsnfsTer2	frameshift	Exon 8 of 23	ENSP00000482968.1
	ALMS1	ENST00000484298.5	TSL:1	c.2095dupA	p.Thr699AsnfsTer2	frameshift	Exon 7 of 22	ENSP00000478155.1
	ALMS1	ENST00000684548.1		c.1840dupA	p.Thr614AsnfsTer2	frameshift	Exon 6 of 21	ENSP00000507421.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 249020 AF XY: 0.00000740

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000688 AC: 10 AN: 1453110 Hom.: 0 Cov.: 40 AF XY: 0.00000692 AC XY: 5 AN XY: 722584

African (AFR) AF: 0.00 AC: 0 AN: 33372

American (AMR) AF: 0.00 AC: 0 AN: 43868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25832

East Asian (EAS) AF: 0.00 AC: 0 AN: 39364

South Asian (SAS) AF: 0.00 AC: 0 AN: 85684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00000904 AC: 10 AN: 1106092

Other (OTH) AF: 0.00 AC: 0 AN: 59952

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000816 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Alstrom syndrome (3)
1	-	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.085
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs769291842; hg19: chr2-73675874;