chr9-131511394-G-A

Variant names:

• chr9-131511394-G-A
• rs4740164
• NM_001077365.2:c.913G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001077365.2(POMT1):​c.913G>A​(p.Val305Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0467 in 1,614,046 control chromosomes in the GnomAD database, including 2,249 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (243 hom., cov: 33)
  • Exomes 𝑓: 0.047 (2006 hom.)
• Consequence: POMT1 NM_001077365.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 4.94
• Publications: 32 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: Ambry Genetics, Laboratory for Molecular Medicine, Genomics England PanelApp, G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016653538).
• BP6: Variant 9-131511394-G-A is Benign according to our data. Variant chr9-131511394-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077365.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT1	NM_001077365.2	MANE Select	c.913G>A	p.Val305Ile	missense	Exon 10 of 20	NP_001070833.1	A0A140VKE0
	POMT1	NM_001353193.2		c.979G>A	p.Val327Ile	missense	Exon 10 of 20	NP_001340122.2	Q9Y6A1-1
	POMT1	NM_007171.4		c.979G>A	p.Val327Ile	missense	Exon 10 of 20	NP_009102.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT1	ENST00000402686.8	TSL:1 MANE Select	c.913G>A	p.Val305Ile	missense	Exon 10 of 20	ENSP00000385797.4	Q9Y6A1-2
	POMT1	ENST00000372228.9	TSL:1	c.979G>A	p.Val327Ile	missense	Exon 10 of 20	ENSP00000361302.3	Q9Y6A1-1
	POMT1	ENST00000423007.6	TSL:1	c.970G>A	p.Val324Ile	missense	Exon 9 of 19	ENSP00000404119.2	A0A1V1FTP4

Frequencies

GnomAD3 genomes AF: 0.0436 AC: 6632 AN: 152166 Hom.: 244 Cov.: 33

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0556

Gnomad EAS AF: 0.0768

Gnomad SAS AF: 0.0280

Gnomad FIN AF: 0.0224

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0450

Gnomad OTH AF: 0.0551

GnomAD2 exomes AF: 0.0567 AC: 14271 AN: 251494 AF XY: 0.0534

Gnomad AFR exome AF: 0.0170

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.0548

Gnomad EAS exome AF: 0.0813

Gnomad FIN exome AF: 0.0230

Gnomad NFE exome AF: 0.0461

Gnomad OTH exome AF: 0.0594

GnomAD4 exome AF: 0.0470 AC: 68688 AN: 1461762 Hom.: 2006 Cov.: 38 AF XY: 0.0462 AC XY: 33562 AN XY: 727190

African (AFR) AF: 0.0173 AC: 580 AN: 33480

American (AMR) AF: 0.141 AC: 6288 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0547 AC: 1430 AN: 26136

East Asian (EAS) AF: 0.0795 AC: 3154 AN: 39696

South Asian (SAS) AF: 0.0281 AC: 2420 AN: 86252

European-Finnish (FIN) AF: 0.0238 AC: 1270 AN: 53418

Middle Eastern (MID) AF: 0.0465 AC: 268 AN: 5760

European-Non Finnish (NFE) AF: 0.0450 AC: 50032 AN: 1111906

Other (OTH) AF: 0.0537 AC: 3246 AN: 60392

GnomAD4 genome AF: 0.0435 AC: 6627 AN: 152284 Hom.: 243 Cov.: 33 AF XY: 0.0440 AC XY: 3278 AN XY: 74468

African (AFR) AF: 0.0170 AC: 707 AN: 41548

American (AMR) AF: 0.111 AC: 1696 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0556 AC: 193 AN: 3472

East Asian (EAS) AF: 0.0768 AC: 398 AN: 5184

South Asian (SAS) AF: 0.0278 AC: 134 AN: 4820

European-Finnish (FIN) AF: 0.0224 AC: 238 AN: 10612

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0450 AC: 3059 AN: 68026

Other (OTH) AF: 0.0540 AC: 114 AN: 2110

Alfa AF: 0.0479 Hom.: 849

Bravo AF: 0.0514

TwinsUK AF: 0.0399 AC: 148

ALSPAC AF: 0.0431 AC: 166

ESP6500AA AF: 0.0209 AC: 92

ESP6500EA AF: 0.0464 AC: 399

ExAC AF: 0.0533 AC: 6471

Asia WGS AF: 0.0580 AC: 203 AN: 3478

EpiCase AF: 0.0496

EpiControl AF: 0.0513

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2K (2)
-	-	2	not provided (2)
-	-	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	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	0.070
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Benign	0.22
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
PhyloP100		4.9
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.24
Sift	Benign	0.86	T
Sift4G	Benign	0.24	T
ClinPred		0.016	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.019
Mutation Taster		=98/2	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: rs4740164; hg19: chr9-134386781; COSMIC: COSV107420832;