NM_001077365.2:c.891G>A

Variant names:

• chr9-131511372-G-A
• rs76109289
• NM_001077365.2:c.891G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001077365.2(POMT1):​c.891G>A​(p.Leu297Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,613,924 control chromosomes in the GnomAD database, including 250 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L297L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0065 (36 hom., cov: 34)
  • Exomes 𝑓: 0.0035 (214 hom.)
• Consequence: POMT1 NM_001077365.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.235
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002196163).
• BP6: Variant 9-131511372-G-A is Benign according to our data. Variant chr9-131511372-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.235 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0821 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.891G>A	p.Leu297Leu	synonymous	Exon 10 of 20	NP_001070833.1	A0A140VKE0
	POMT1	NM_001374689.1		c.874G>A	p.Gly292Arg	missense	Exon 9 of 19	NP_001361618.1
	POMT1	NM_001353193.2		c.957G>A	p.Leu319Leu	synonymous	Exon 10 of 20	NP_001340122.2	Q9Y6A1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT1	ENST00000402686.8	TSL:1 MANE Select	c.891G>A	p.Leu297Leu	synonymous	Exon 10 of 20	ENSP00000385797.4	Q9Y6A1-2
	POMT1	ENST00000372228.9	TSL:1	c.957G>A	p.Leu319Leu	synonymous	Exon 10 of 20	ENSP00000361302.3	Q9Y6A1-1
	POMT1	ENST00000423007.6	TSL:1	c.948G>A	p.Leu316Leu	synonymous	Exon 9 of 19	ENSP00000404119.2	A0A1V1FTP4

Frequencies

GnomAD3 genomes AF: 0.00644 AC: 980 AN: 152210 Hom.: 34 Cov.: 34

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0505

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0167

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.0137 AC: 3456 AN: 251486 AF XY: 0.0106

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.0882

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0134

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00929

GnomAD4 exome AF: 0.00346 AC: 5054 AN: 1461596 Hom.: 214 Cov.: 38 AF XY: 0.00298 AC XY: 2169 AN XY: 727124

African (AFR) AF: 0.00137 AC: 46 AN: 33476

American (AMR) AF: 0.0843 AC: 3772 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0208 AC: 825 AN: 39694

South Asian (SAS) AF: 0.000580 AC: 50 AN: 86248

European-Finnish (FIN) AF: 0.00137 AC: 73 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.0000729 AC: 81 AN: 1111756

Other (OTH) AF: 0.00339 AC: 205 AN: 60386

GnomAD4 genome AF: 0.00649 AC: 989 AN: 152328 Hom.: 36 Cov.: 34 AF XY: 0.00695 AC XY: 518 AN XY: 74480

African (AFR) AF: 0.00190 AC: 79 AN: 41570

American (AMR) AF: 0.0510 AC: 781 AN: 15300

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

East Asian (EAS) AF: 0.0168 AC: 87 AN: 5190

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68028

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.0101 Hom.: 799

Bravo AF: 0.0114

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.0104 AC: 1260

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	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	Benign	0.21
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Benign	0.018
Eigen_PC	Benign	0.024
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0022	T
MetaSVM	Uncertain	-0.11	T
PhyloP100		0.23
PROVEAN	Benign	0.38	N
REVEL	Benign	0.16
Sift	Benign	0.13	T
Sift4G	Benign	0.51	T
MutPred		0.28		Gain of MoRF binding (P = 0.052)
ClinPred		0.0092	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs76109289; hg19: chr9-134386759;