chr9-131522987-G-A

Variant names:

• chr9-131522987-G-A
• rs535544133
• NM_001077365.2:c.2059G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007171.4(POMT1):​c.2125G>A​(p.Ala709Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,606,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A709V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: POMT1 NM_007171.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.30
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.165786).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007171.4. 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.2059G>A	p.Ala687Thr	missense	Exon 20 of 20	NP_001070833.1
	POMT1	NM_001353193.2		c.2125G>A	p.Ala709Thr	missense	Exon 20 of 20	NP_001340122.2
	POMT1	NM_007171.4		c.2125G>A	p.Ala709Thr	missense	Exon 20 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.2059G>A	p.Ala687Thr	missense	Exon 20 of 20	ENSP00000385797.4
	POMT1	ENST00000372228.9	TSL:1	c.2125G>A	p.Ala709Thr	missense	Exon 20 of 20	ENSP00000361302.3
	POMT1	ENST00000423007.6	TSL:1	c.2116G>A	p.Ala706Thr	missense	Exon 19 of 19	ENSP00000404119.2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000620 AC: 15 AN: 241978 AF XY: 0.0000534

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000274

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000273

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000206 AC: 30 AN: 1453848 Hom.: 0 Cov.: 34 AF XY: 0.0000277 AC XY: 20 AN XY: 722812

African (AFR) AF: 0.0000300 AC: 1 AN: 33354

American (AMR) AF: 0.000159 AC: 7 AN: 44164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39668

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51288

Middle Eastern (MID) AF: 0.000240 AC: 1 AN: 4162

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1109962

Other (OTH) AF: 0.0000333 AC: 2 AN: 60062

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74460

African (AFR) AF: 0.0000241 AC: 1 AN: 41544

American (AMR) AF: 0.000131 AC: 2 AN: 15300

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

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2K;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1;C5436962:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	not specified (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	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.012
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.78	N
REVEL	Uncertain	0.31
Sift	Benign	0.031	D
Sift4G	Uncertain	0.022	D
Polyphen		0.94	P
Vest4		0.28
MutPred		0.46		Gain of glycosylation at A709 (P = 0.0721)
MVP		0.91
MPC		0.33
ClinPred		0.065	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.35
Mutation Taster		=93/7	polymorphism

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: rs535544133; hg19: chr9-134398374;