chr2-73385870-T-G

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001378454.1(ALMS1):​c.2T>G​(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 580,402 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• 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 12 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-G is Pathogenic according to our data. Variant chr2-73385870-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 551649.Status of the report is criteria_provided_single_submitter, 1 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>G	p.Met1?	start_lost	Exon 1 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.2T>G	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>G	p.Met1?	start_lost	Exon 1 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.2T>G	p.Met1?	start_lost	Exon 1 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000614410.4	TSL:5	c.2T>G	p.Met1?	start_lost	Exon 1 of 16	ENSP00000479094.1	A0A087WV20

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000345 AC: 2 AN: 580402 Hom.: 0 Cov.: 7 AF XY: 0.00000641 AC XY: 2 AN XY: 312172

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: 19510

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

South Asian (SAS) AF: 0.0000319 AC: 2 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: 0.00 AC: 0 AN: 346710

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Alstrom syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.091	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.97	T
PhyloP100		2.8
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.97		Gain of solvent accessibility (P = 0.11)
MVP		0.52
ClinPred		1.0	D
GERP RS		3.6
PromoterAI		-0.41	Neutral
Varity_R		0.82
gMVP		0.14
Mutation Taster		=36/164	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: rs1553396091; hg19: chr2-73612998;