rs139774354

Variant names:

• chr9-131509995-A-G
• rs139774354
• ENST00000372228.9:c.698A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-131509995-A-G
• chr9-131509995-A-C
• chr9-131509995-A-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001077365.2(POMT1):​c.698A>G​(p.Asn233Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000589 in 1,614,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. N233N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: POMT1 NM_001077365.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.01
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056280166).

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.698A>G	p.Asn233Ser	missense splice_region	Exon 8 of 20	NP_001070833.1	A0A140VKE0
	POMT1	NM_001353193.2		c.698A>G	p.Asn233Ser	missense	Exon 8 of 20	NP_001340122.2	Q9Y6A1-1
	POMT1	NM_007171.4		c.698A>G	p.Asn233Ser	missense	Exon 8 of 20	NP_009102.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT1	ENST00000372228.9	TSL:1	c.698A>G	p.Asn233Ser	missense	Exon 8 of 20	ENSP00000361302.3	Q9Y6A1-1
	POMT1	ENST00000423007.6	TSL:1	c.689A>G	p.Asn230Ser	missense	Exon 7 of 19	ENSP00000404119.2	A0A1V1FTP4
	POMT1	ENST00000402686.8	TSL:1 MANE Select	c.698A>G	p.Asn233Ser	missense splice_region	Exon 8 of 20	ENSP00000385797.4	Q9Y6A1-2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000115 AC: 29 AN: 251440 AF XY: 0.000110

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000575 AC: 84 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.0000619 AC XY: 45 AN XY: 727208

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

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

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1111930

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74462

African (AFR) AF: 0.000120 AC: 5 AN: 41562

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000567 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	Benign	0.068
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.5	L
PhyloP100		5.0
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.28
Sift	Benign	0.15	T
Sift4G	Benign	0.34	T
Polyphen		0.014	B
Vest4		0.35
MVP		0.78
MPC		0.21
ClinPred		0.026	T
GERP RS		3.2
PromoterAI		-0.0068	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.074
gMVP		0.13
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs139774354; hg19: chr9-134385382;