rs117985576

Variant names:

• chr9-131519401-G-A
• rs117985576
• NM_001077365.2:c.1499G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001077365.2(POMT1):​c.1499G>A​(p.Arg500Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 1,552,060 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (17 hom.)
• Consequence: POMT1 NM_001077365.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:12
• Conservation: PhyloP100: 1.28
• Publications: 9 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 9-131519401-G-A is Benign according to our data. Variant chr9-131519401-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95459.
• BS2: High Homozygotes in GnomAdExome4 at 17 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.1499G>A	p.Arg500Lys	missense	Exon 16 of 20	NP_001070833.1	A0A140VKE0
	POMT1	NM_001353193.2		c.1565G>A	p.Arg522Lys	missense	Exon 16 of 20	NP_001340122.2	Q9Y6A1-1
	POMT1	NM_007171.4		c.1565G>A	p.Arg522Lys	missense	Exon 16 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.1499G>A	p.Arg500Lys	missense	Exon 16 of 20	ENSP00000385797.4	Q9Y6A1-2
	POMT1	ENST00000372228.9	TSL:1	c.1565G>A	p.Arg522Lys	missense	Exon 16 of 20	ENSP00000361302.3	Q9Y6A1-1
	POMT1	ENST00000423007.6	TSL:1	c.1556G>A	p.Arg519Lys	missense	Exon 15 of 19	ENSP00000404119.2	A0A1V1FTP4

Frequencies

GnomAD3 genomes AF: 0.00173 AC: 264 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00326

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00169 AC: 266 AN: 157036 AF XY: 0.00159

Gnomad AFR exome AF: 0.000560

Gnomad AMR exome AF: 0.00178

Gnomad ASJ exome AF: 0.000235

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00332

Gnomad OTH exome AF: 0.00202

GnomAD4 exome AF: 0.00264 AC: 3696 AN: 1399756 Hom.: 17 Cov.: 32 AF XY: 0.00252 AC XY: 1743 AN XY: 690428

African (AFR) AF: 0.000536 AC: 17 AN: 31698

American (AMR) AF: 0.00176 AC: 63 AN: 35714

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25182

East Asian (EAS) AF: 0.0000278 AC: 1 AN: 35948

South Asian (SAS) AF: 0.000252 AC: 20 AN: 79268

European-Finnish (FIN) AF: 0.000163 AC: 8 AN: 48984

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5700

European-Non Finnish (NFE) AF: 0.00321 AC: 3462 AN: 1079204

Other (OTH) AF: 0.00210 AC: 122 AN: 58058

GnomAD4 genome AF: 0.00173 AC: 264 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74474

African (AFR) AF: 0.000409 AC: 17 AN: 41564

American (AMR) AF: 0.000980 AC: 15 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00326 AC: 222 AN: 68036

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00277 Hom.: 2

Bravo AF: 0.00192

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000469 AC: 2

ESP6500EA AF: 0.00132 AC: 11

ExAC AF: 0.000432 AC: 39

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	7	not provided (8)
-	1	3	not specified (4)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2K (1)
-	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	-	Intellectual disability (1)
-	1	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 (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	0.059
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.8
DANN	Benign	0.86
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-0.53	N
PhyloP100		1.3
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.99	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.21
MVP		0.43
MPC		0.25
ClinPred		0.0029	T
GERP RS		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.22
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs117985576; hg19: chr9-134394788;