9-131511357-T-C

Variant names:

• chr9-131511357-T-C
• rs10901065
• NM_001077365.2:c.876T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000402686.8(POMT1):​c.876T>C​(p.Thr292Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.94 in 1,613,692 control chromosomes in the GnomAD database, including 714,864 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60625 hom., cov: 31)
  • Exomes 𝑓: 0.95 (654239 hom.)
• Consequence: POMT1 ENST00000402686.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.67
• Publications: 33 publications found

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]

POMT1 Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Laboratory for Molecular Medicine, Genomics England PanelApp
• myopathy caused by variation in POMT1

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal recessive limb-girdle muscular dystrophy type 2K

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy with cerebellar involvement

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy with intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy without intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscle-eye-brain disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.0885815E-7).
• BP6: Variant 9-131511357-T-C is Benign according to our data. Variant chr9-131511357-T-C is described in ClinVar as Benign. ClinVar VariationId is 167519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.67 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.948 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000402686.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT1	NM_001077365.2	MANE Select	c.876T>C	p.Thr292Thr	synonymous	Exon 10 of 20	NP_001070833.1
	POMT1	NM_001374689.1		c.859T>C	p.Ser287Pro	missense	Exon 9 of 19	NP_001361618.1
	POMT1	NM_001353193.2		c.942T>C	p.Thr314Thr	synonymous	Exon 10 of 20	NP_001340122.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT1	ENST00000402686.8	TSL:1 MANE Select	c.876T>C	p.Thr292Thr	synonymous	Exon 10 of 20	ENSP00000385797.4
	POMT1	ENST00000372228.9	TSL:1	c.942T>C	p.Thr314Thr	synonymous	Exon 10 of 20	ENSP00000361302.3
	POMT1	ENST00000423007.6	TSL:1	c.933T>C	p.Thr311Thr	synonymous	Exon 9 of 19	ENSP00000404119.2

Frequencies

GnomAD3 genomes AF: 0.888 AC: 134957 AN: 152044 Hom.: 60594 Cov.: 31

Gnomad AFR AF: 0.746

Gnomad AMI AF: 0.899

Gnomad AMR AF: 0.861

Gnomad ASJ AF: 0.942

Gnomad EAS AF: 0.918

Gnomad SAS AF: 0.970

Gnomad FIN AF: 0.978

Gnomad MID AF: 0.915

Gnomad NFE AF: 0.954

Gnomad OTH AF: 0.895

GnomAD2 exomes AF: 0.924 AC: 232276 AN: 251438 AF XY: 0.932

Gnomad AFR exome AF: 0.735

Gnomad AMR exome AF: 0.841

Gnomad ASJ exome AF: 0.943

Gnomad EAS exome AF: 0.914

Gnomad FIN exome AF: 0.977

Gnomad NFE exome AF: 0.953

Gnomad OTH exome AF: 0.931

GnomAD4 exome AF: 0.945 AC: 1381478 AN: 1461530 Hom.: 654239 Cov.: 56 AF XY: 0.947 AC XY: 688522 AN XY: 727046

African (AFR) AF: 0.733 AC: 24514 AN: 33466

American (AMR) AF: 0.842 AC: 37663 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.942 AC: 24632 AN: 26136

East Asian (EAS) AF: 0.916 AC: 36369 AN: 39686

South Asian (SAS) AF: 0.971 AC: 83715 AN: 86254

European-Finnish (FIN) AF: 0.976 AC: 52148 AN: 53418

Middle Eastern (MID) AF: 0.936 AC: 5393 AN: 5762

European-Non Finnish (NFE) AF: 0.954 AC: 1061016 AN: 1111720

Other (OTH) AF: 0.928 AC: 56028 AN: 60374

GnomAD4 genome AF: 0.887 AC: 135030 AN: 152162 Hom.: 60625 Cov.: 31 AF XY: 0.889 AC XY: 66157 AN XY: 74396

African (AFR) AF: 0.746 AC: 30922 AN: 41456

American (AMR) AF: 0.861 AC: 13165 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.942 AC: 3269 AN: 3472

East Asian (EAS) AF: 0.918 AC: 4746 AN: 5172

South Asian (SAS) AF: 0.971 AC: 4683 AN: 4824

European-Finnish (FIN) AF: 0.978 AC: 10368 AN: 10606

Middle Eastern (MID) AF: 0.915 AC: 269 AN: 294

European-Non Finnish (NFE) AF: 0.954 AC: 64891 AN: 68026

Other (OTH) AF: 0.897 AC: 1897 AN: 2116

Alfa AF: 0.924 Hom.: 134745

Bravo AF: 0.869

TwinsUK AF: 0.960 AC: 3559

ALSPAC AF: 0.955 AC: 3682

ESP6500AA AF: 0.741 AC: 3263

ESP6500EA AF: 0.952 AC: 8189

ExAC AF: 0.923 AC: 112067

Asia WGS AF: 0.917 AC: 3189 AN: 3478

EpiCase AF: 0.949

EpiControl AF: 0.947

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2K (1)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 (1)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 (1)
-	-	1	not provided (1)
-	-	1	Walker-Warburg congenital muscular dystrophy;C1836373:Autosomal recessive limb-girdle muscular dystrophy type 2K;C5436962:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	1.7
DANN	Benign	0.95
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	8.1e-7	T
MetaSVM	Benign	-0.98	T
PhyloP100		-1.7
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.014	D
Sift4G	Benign	0.33	T
ClinPred		0.0064	T
GERP RS		0.21
Mutation Taster		=100/0	polymorphism (auto)

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: rs10901065; hg19: chr9-134386744; COSMIC: COSV108169145; COSMIC: COSV108169145;