2-73385869-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_001378454.1(ALMS1):c.1A>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 0.0000017 in 589,222 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

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 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_001378454.1 (ALMS1) was described as [Likely_pathogenic] in ClinVar as 1064980
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.1A>G	p.Met1?	start_lost	1/23	ENST00000613296.6
ALMS1	NM_015120.4	c.1A>G	p.Met1?	start_lost	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.1A>G	p.Met1?	start_lost	1/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000170 AC: 1 AN: 589222 Hom.: 0 Cov.: 7 AF XY: 0.00000316 AC XY: 1 AN XY: 316718

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000283

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alstrom syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 27, 2022

This sequence change affects the initiator methionine of the ALMS1 mRNA. The next in-frame methionine is located at codon 163. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.038	T;T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.82
MVP		0.50
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.50
gMVP		0.062

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-73612997;