rs562345472

chr2-73419259-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001378454.1(ALMS1):c.587C>T(p.Thr196Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T196T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.531

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1841783).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.587C>T	p.Thr196Met	missense_variant	3/23	ENST00000613296.6
ALMS1	NM_015120.4	c.590C>T	p.Thr197Met	missense_variant	3/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.587C>T	p.Thr196Met	missense_variant	3/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 248988 Hom.: 0 AF XY: 0.0000444 AC XY: 6 AN XY: 135076

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461702 Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23 AN XY: 727152

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74462

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alstrom syndrome Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 23, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 30, 2022	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 197 of the ALMS1 protein (p.Thr197Met). This variant is present in population databases (rs562345472, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 459874). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 17, 2022	- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2022

The p.T197M variant (also known as c.590C>T), located in coding exon 3 of the ALMS1 gene, results from a C to T substitution at nucleotide position 590. The threonine at codon 197 is replaced by methionine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	19
Dann	Benign	0.96
DEOGEN2	Benign	0.037	T;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.52
MutPred		0.24		.;Loss of phosphorylation at T196 (P = 0.1684);Loss of phosphorylation at T196 (P = 0.1684);
MVP		0.53
ClinPred		0.25	T
GERP RS		1.6
Varity_R		0.022
gMVP		0.14

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: rs562345472; hg19: chr2-73646387; COSMIC: COSV105092346;