rs1553396091

Variant names:

• chr2-73385870-T-C
• rs1553396091
• NM_001378454.1:c.2T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-73385870-T-C
• chr2-73385870-T-G
• chr2-73385870-T-A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001378454.1(ALMS1):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 580,404 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 Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 start_lost
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.79
• 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, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ENSG00000285068 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 46 pathogenic variants. Next in-frame start position is after 162 codons. Genomic position: 73419156. Lost 0.039 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-73385870-T-C is Pathogenic according to our data. Variant chr2-73385870-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4059264.Status of the report is no_assertion_criteria_provided, 0 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	NM_001378454.1	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.2T>C	p.Met1?	start_lost	Exon 1 of 23	NP_055935.4	Q8TCU4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 1 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000614410.4	TSL:5	c.2T>C	p.Met1?	start_lost	Exon 1 of 16	ENSP00000479094.1	A0A087WV20

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000345 AC: 2 AN: 580404 Hom.: 0 Cov.: 7 AF XY: 0.00000320 AC XY: 1 AN XY: 312174

African (AFR) AF: 0.00 AC: 0 AN: 16078

American (AMR) AF: 0.00 AC: 0 AN: 33962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19512

East Asian (EAS) AF: 0.00 AC: 0 AN: 31068

South Asian (SAS) AF: 0.00 AC: 0 AN: 62692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2470

European-Non Finnish (NFE) AF: 0.00000577 AC: 2 AN: 346710

Other (OTH) AF: 0.00 AC: 0 AN: 30674

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Alstrom syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.091	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.97	T
PhyloP100		2.8
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.98		Gain of phosphorylation at M1 (P = 0.002)
MVP		0.58
ClinPred		0.99	D
GERP RS		3.6
PromoterAI		-0.38	Neutral
Varity_R		0.46
gMVP		0.082
Mutation Taster		=36/164	disease causing

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: rs1553396091; hg19: chr2-73612998;