rs11243406

Variant names:

• chr9-131515483-C-A
• rs11243406
• NM_001077365.2:c.1233C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-131515483-C-A
• chr9-131515483-C-G
• chr9-131515483-C-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001077365.2(POMT1):​c.1233C>A​(p.Asp411Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0497 in 1,614,088 control chromosomes in the GnomAD database, including 2,326 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (129 hom., cov: 33)
  • Exomes 𝑓: 0.051 (2197 hom.)
• Consequence: POMT1 NM_001077365.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.94
• Publications: 15 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: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001077365.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.008095145).
• BP6: Variant 9-131515483-C-A is Benign according to our data. Variant chr9-131515483-C-A is described in ClinVar as Benign. ClinVar VariationId is 95455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0559 is higher than 0.05.

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.1233C>A	p.Asp411Glu	missense	Exon 13 of 20	NP_001070833.1	A0A140VKE0
	POMT1	NM_001353193.2		c.1299C>A	p.Asp433Glu	missense	Exon 13 of 20	NP_001340122.2	Q9Y6A1-1
	POMT1	NM_007171.4		c.1299C>A	p.Asp433Glu	missense	Exon 13 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.1233C>A	p.Asp411Glu	missense	Exon 13 of 20	ENSP00000385797.4	Q9Y6A1-2
	POMT1	ENST00000372228.9	TSL:1	c.1299C>A	p.Asp433Glu	missense	Exon 13 of 20	ENSP00000361302.3	Q9Y6A1-1
	POMT1	ENST00000423007.6	TSL:1	c.1290C>A	p.Asp430Glu	missense	Exon 12 of 19	ENSP00000404119.2	A0A1V1FTP4

Frequencies

GnomAD3 genomes AF: 0.0361 AC: 5498 AN: 152222 Hom.: 129 Cov.: 33

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.0572

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0574

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0348 AC: 8756 AN: 251496 AF XY: 0.0356

Gnomad AFR exome AF: 0.00960

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0557

Gnomad NFE exome AF: 0.0533

Gnomad OTH exome AF: 0.0319

GnomAD4 exome AF: 0.0511 AC: 74727 AN: 1461748 Hom.: 2197 Cov.: 32 AF XY: 0.0505 AC XY: 36720 AN XY: 727170

African (AFR) AF: 0.00762 AC: 255 AN: 33480

American (AMR) AF: 0.0144 AC: 644 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 482 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0157 AC: 1353 AN: 86258

European-Finnish (FIN) AF: 0.0533 AC: 2848 AN: 53410

Middle Eastern (MID) AF: 0.00746 AC: 43 AN: 5766

European-Non Finnish (NFE) AF: 0.0598 AC: 66523 AN: 1111886

Other (OTH) AF: 0.0426 AC: 2573 AN: 60390

GnomAD4 genome AF: 0.0361 AC: 5496 AN: 152340 Hom.: 129 Cov.: 33 AF XY: 0.0348 AC XY: 2593 AN XY: 74496

African (AFR) AF: 0.0104 AC: 433 AN: 41582

American (AMR) AF: 0.0217 AC: 332 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0153 AC: 74 AN: 4834

European-Finnish (FIN) AF: 0.0572 AC: 607 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0574 AC: 3903 AN: 68022

Other (OTH) AF: 0.0265 AC: 56 AN: 2112

Alfa AF: 0.0466 Hom.: 900

Bravo AF: 0.0316

TwinsUK AF: 0.0618 AC: 229

ALSPAC AF: 0.0636 AC: 245

ESP6500AA AF: 0.0107 AC: 47

ESP6500EA AF: 0.0495 AC: 426

ExAC AF: 0.0342 AC: 4147

Asia WGS AF: 0.00520 AC: 19 AN: 3478

EpiCase AF: 0.0493

EpiControl AF: 0.0510

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	0.056
Eigen_PC	Benign	-0.063
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.61
MutPred		0.35		Gain of sheet (P = 0.1208)
MPC		0.75
ClinPred		0.025	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.43
Mutation Taster		=80/20	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11243406; hg19: chr9-134390870; COSMIC: COSV61225493; COSMIC: COSV61225493;