rs12115566

chr9-131522077-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001077365.2(POMT1):c.1856C>T(p.Ala619Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00491 in 1,614,056 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A619A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (59 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (48 hom.)
• Consequence: POMT1 NM_001077365.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.797

Genes affected

POMT1 (HGNC:9202): (protein O-mannosyltransferase 1) The protein encoded by this gene is an O-mannosyltransferase that requires interaction with the product of the POMT2 gene for enzymatic function. The encoded protein is found in the membrane of the endoplasmic reticulum. Defects in this gene are a cause of Walker-Warburg syndrome (WWS) and limb-girdle muscular dystrophy type 2K (LGMD2K). Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031572282).
• BP6: Variant 9-131522077-C-T is Benign according to our data. Variant chr9-131522077-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 130011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-131522077-C-T is described in Lovd as [Likely_benign]. Variant chr9-131522077-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0154 (2352/152268) while in subpopulation AFR AF= 0.0477 (1983/41540). AF 95% confidence interval is 0.046. There are 59 homozygotes in gnomad4. There are 1138 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 58 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMT1	NM_001077365.2	c.1856C>T	p.Ala619Val	missense_variant	19/20	ENST00000402686.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMT1	ENST00000402686.8	c.1856C>T	p.Ala619Val	missense_variant	19/20	1	NM_001077365.2	P1
	ENST00000415423.1	n.62+91G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2343 AN: 152150 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.0476

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00273

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00665 AC: 1671 AN: 251270 Hom.: 33 AF XY: 0.00628 AC XY: 853 AN XY: 135866

Gnomad AFR exome AF: 0.0489

Gnomad AMR exome AF: 0.00477

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00787

Gnomad FIN exome AF: 0.000603

Gnomad NFE exome AF: 0.00335

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00381 AC: 5571 AN: 1461788 Hom.: 48 Cov.: 31 AF XY: 0.00393 AC XY: 2861 AN XY: 727194

Gnomad4 AFR exome AF: 0.0476

Gnomad4 AMR exome AF: 0.00501

Gnomad4 ASJ exome AF: 0.00440

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00813

Gnomad4 FIN exome AF: 0.000900

Gnomad4 NFE exome AF: 0.00218

Gnomad4 OTH exome AF: 0.00662

GnomAD4 genome AF: 0.0154 AC: 2352 AN: 152268 Hom.: 59 Cov.: 33 AF XY: 0.0153 AC XY: 1138 AN XY: 74472

Gnomad4 AFR AF: 0.0477

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.00606

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00787

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00273

Gnomad4 OTH AF: 0.0157

Alfa AF: 0.00531 Hom.: 18

Bravo AF: 0.0168

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.0415 AC: 183

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00757 AC: 919

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00379

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 01, 2017	- -

Autosomal recessive limb-girdle muscular dystrophy type 2K Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Walker-Warburg congenital muscular dystrophy;C1836373:Autosomal recessive limb-girdle muscular dystrophy type 2K;C5436962:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	6.2
Dann	Benign	0.93
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.39	T;T;T;T;.;T
MetaRNN	Benign	0.0032	T;T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.93	N;N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.32	T;T;T;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T;T
Polyphen		0.012, 0.032	.;B;.;B;B;.
Vest4		0.19
MVP		0.82
MPC		0.25
ClinPred		0.0026	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.22

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: rs12115566; hg19: chr9-134397464;