rs35242383

Variant names:

• chr9-131513281-C-G
• rs35242383
• NM_001077365.2:c.1125C>G

Your query was ambiguous. Multiple possible variants found:

• chr9-131513281-C-G
• chr9-131513281-C-T
• chr9-131513281-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001077365.2(POMT1):​c.1125C>G​(p.His375Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000938 in 1,460,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. H375H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000094 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POMT1 NM_001077365.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -1.90
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

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.1125C>G	p.His375Gln	missense	Exon 12 of 20	NP_001070833.1	A0A140VKE0
	POMT1	NM_001353193.2		c.1191C>G	p.His397Gln	missense	Exon 12 of 20	NP_001340122.2	Q9Y6A1-1
	POMT1	NM_007171.4		c.1191C>G	p.His397Gln	missense	Exon 12 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.1125C>G	p.His375Gln	missense	Exon 12 of 20	ENSP00000385797.4	Q9Y6A1-2
	POMT1	ENST00000372228.9	TSL:1	c.1191C>G	p.His397Gln	missense	Exon 12 of 20	ENSP00000361302.3	Q9Y6A1-1
	POMT1	ENST00000423007.6	TSL:1	c.1182C>G	p.His394Gln	missense	Exon 11 of 19	ENSP00000404119.2	A0A1V1FTP4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152034 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249334 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000938 AC: 137 AN: 1460850 Hom.: 0 Cov.: 32 AF XY: 0.0000894 AC XY: 65 AN XY: 726752

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000122 AC: 136 AN: 1111988

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152034 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74250

African (AFR) AF: 0.00 AC: 0 AN: 41374

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 3

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (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	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	3.7
DANN	Benign	0.90
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		-1.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.88
MutPred		0.46		Gain of disorder (P = 0.1427)
MVP		0.61
MPC		0.90
ClinPred		0.42	T
GERP RS		-6.8
Varity_R		0.64
gMVP		0.59
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35242383; hg19: chr9-134388668;