rs752880907

chr9-131507476-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001077365.2(POMT1):c.389A>C(p.His130Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,613,794 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: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: POMT1 NM_001077365.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.21

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMT1	NM_001077365.2	c.389A>C	p.His130Pro	missense_variant	5/20	ENST00000402686.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMT1	ENST00000402686.8	c.389A>C	p.His130Pro	missense_variant	5/20	1	NM_001077365.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151920 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251494 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.0000220 AC XY: 16 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.0000225

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151920 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74168

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000948

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000642

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 24, 2022

This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 130 of the POMT1 protein (p.His130Pro). This variant is present in population databases (rs752880907, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with POMT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 471382). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	T;T;T;T;T;.;T;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.015	D;D;D;D;D;D;D;D;T;T
Sift4G	Uncertain	0.057	T;T;D;T;T;T;D;D;T;D
Polyphen		0.90, 0.99	.;P;.;.;D;P;.;.;.;.
Vest4		0.55
MutPred		0.50		.;Loss of helix (P = 0.1706);.;.;Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);.;.;.;
MVP		0.95
MPC		0.42
ClinPred		0.62	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.74
gMVP		0.90

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: rs752880907; hg19: chr9-134382863;