rs34954751

Variant names:

• chr9-131520187-G-A
• rs34954751
• NM_001077365.2:c.1692G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001077365.2(POMT1):​c.1692G>A​(p.Arg564Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 1,612,506 control chromosomes in the GnomAD database, including 773 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (55 hom., cov: 32)
  • Exomes 𝑓: 0.029 (718 hom.)
• Consequence: POMT1 NM_001077365.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.111
• Publications: 7 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

ENSG00000230289 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 9-131520187-G-A is Benign according to our data. Variant chr9-131520187-G-A is described in ClinVar as Benign. ClinVar VariationId is 130008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.111 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0217 (3302/152286) while in subpopulation NFE AF = 0.0309 (2105/68018). AF 95% confidence interval is 0.0298. There are 55 homozygotes in GnomAd4. There are 1620 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 55 AR gene

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.1692G>A	p.Arg564Arg	synonymous	Exon 17 of 20	NP_001070833.1	A0A140VKE0
	POMT1	NM_001353193.2		c.1758G>A	p.Arg586Arg	synonymous	Exon 17 of 20	NP_001340122.2	Q9Y6A1-1
	POMT1	NM_007171.4		c.1758G>A	p.Arg586Arg	synonymous	Exon 17 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.1692G>A	p.Arg564Arg	synonymous	Exon 17 of 20	ENSP00000385797.4	Q9Y6A1-2
	POMT1	ENST00000372228.9	TSL:1	c.1758G>A	p.Arg586Arg	synonymous	Exon 17 of 20	ENSP00000361302.3	Q9Y6A1-1
	POMT1	ENST00000423007.6	TSL:1	c.1749G>A	p.Arg583Arg	synonymous	Exon 16 of 19	ENSP00000404119.2	A0A1V1FTP4

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3302 AN: 152168 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.00541

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.0487

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0309

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0228 AC: 5711 AN: 250686 AF XY: 0.0232

Gnomad AFR exome AF: 0.00513

Gnomad AMR exome AF: 0.0159

Gnomad ASJ exome AF: 0.00537

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0484

Gnomad NFE exome AF: 0.0312

Gnomad OTH exome AF: 0.0251

GnomAD4 exome AF: 0.0290 AC: 42327 AN: 1460220 Hom.: 718 Cov.: 32 AF XY: 0.0285 AC XY: 20671 AN XY: 726468

African (AFR) AF: 0.00502 AC: 168 AN: 33454

American (AMR) AF: 0.0172 AC: 771 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00635 AC: 166 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.0102 AC: 880 AN: 86236

European-Finnish (FIN) AF: 0.0470 AC: 2480 AN: 52780

Middle Eastern (MID) AF: 0.0243 AC: 140 AN: 5764

European-Non Finnish (NFE) AF: 0.0326 AC: 36210 AN: 1111078

Other (OTH) AF: 0.0250 AC: 1509 AN: 60360

GnomAD4 genome AF: 0.0217 AC: 3302 AN: 152286 Hom.: 55 Cov.: 32 AF XY: 0.0218 AC XY: 1620 AN XY: 74450

African (AFR) AF: 0.00539 AC: 224 AN: 41558

American (AMR) AF: 0.0210 AC: 321 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00807 AC: 39 AN: 4830

European-Finnish (FIN) AF: 0.0487 AC: 516 AN: 10606

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0309 AC: 2105 AN: 68018

Other (OTH) AF: 0.0284 AC: 60 AN: 2114

Alfa AF: 0.0267 Hom.: 102

Bravo AF: 0.0197

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.0329

EpiControl AF: 0.0333

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2K (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
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.3
DANN	Benign	0.79
PhyloP100		0.11
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: rs34954751; hg19: chr9-134395574;