dbSNP rs386352332: MTMR8:p.Gly498Val (chrX-64271062-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_017677.4(MTMR8):c.1493G>T(p.Gly498Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000251 in 1,195,937 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G498E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

MTMR8
NM_017677.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.61

Publications

0 publications found

Variant links:

Genes affected

MTMR8 (HGNC:16825): (myotubularin related protein 8) This gene encodes a member of the myotubularin-related family and is part of the MTMR6 subgroup. Family members are dual-specificity phosphatases and the encoded protein contains a phosphoinositide-binding domain (PID) and a SET-interacting domain (SID). Defects in other family members have been found in myotubular myopathic diseases. [provided by RefSeq, Mar 2010]

MTMR8 links:

ENSG00000287370 (HGNC:):

ENSG00000287370 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTMR8	NM_017677.4 link	c.1493G>T	p.Gly498Val	missense_variant	Exon 13 of 14	ENST00000374852.4	NP_060147.2	Q96EF0-1
LOC112268307	XM_047442705.1 link	c.170+23256C>A		intron_variant	Intron 3 of 4		XP_047298661.1
LOC112268307	XM_047442706.1 link	c.126-34504C>A		intron_variant	Intron 2 of 3		XP_047298662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTMR8	ENST00000374852.4 link	c.1493G>T	p.Gly498Val	missense_variant	Exon 13 of 14	1	NM_017677.4	ENSP00000363985.3		Q96EF0-1

Frequencies

GnomAD3 genomes

AF:

0.00000898

AC:

AN:

111402

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000959

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000611

AC:

AN:

163664

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000419

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000184

AC:

AN:

1084535

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

351501

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25906

American (AMR)

AF:

0.0000607

AC:

AN:

32949

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18748

East Asian (EAS)

AF:

0.00

AC:

AN:

29621

South Asian (SAS)

AF:

0.00

AC:

AN:

51070

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4061

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

836394

Other (OTH)

AF:

0.00

AC:

AN:

45536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000898

AC:

AN:

111402

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33576

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30646

American (AMR)

AF:

0.0000959

AC:

AN:

10425

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3540

South Asian (SAS)

AF:

0.00

AC:

AN:

2635

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5941

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53139

Other (OTH)

AF:

0.00

AC:

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.30

MutationAssessor

Pathogenic

3.7

PhyloP100

2.6

PrimateAI

Benign

0.36

PROVEAN

Pathogenic

-6.1

REVEL

Uncertain

0.62

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

0.98

Vest4

0.79

MutPred

0.39

Gain of MoRF binding (P = 0.2266);

MVP

0.45

MPC

0.0061

ClinPred

0.98

GERP RS

2.9

Varity_R

0.78

gMVP

0.40

Mutation Taster

=82/18

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over