Variant X-64331701-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_017677.4(MTMR8):c.1208T>C(p.Leu403Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000587 in 1,209,196 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000062 ( 0 hom. 22 hem. )

Consequence

MTMR8
NM_017677.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.98

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

BS2

High Hemizygotes in GnomAdExome4 at 22 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTMR8	NM_017677.4 linkuse as main transcript	c.1208T>C	p.Leu403Pro	missense_variant	11/14	ENST00000374852.4	NP_060147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTMR8	ENST00000374852.4 linkuse as main transcript	c.1208T>C	p.Leu403Pro	missense_variant	11/14	1	NM_017677.4	ENSP00000363985	P1	Q96EF0-1
MTMR8	ENST00000462447.5 linkuse as main transcript	n.368T>C		non_coding_transcript_exon_variant	4/4	3
MTMR8	ENST00000478487.5 linkuse as main transcript	n.407T>C		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

112091

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34259

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000165

AC:

AN:

182098

Hom.:

AF XY:

0.00

AC XY:

AN XY:

66756

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000369

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000620

AC:

AN:

1097105

Hom.:

Cov.:

AF XY:

0.0000607

AC XY:

AN XY:

362719

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000749

Gnomad4 OTH exome

AF:

0.000109

GnomAD4 genome

AF:

0.0000268

AC:

AN:

112091

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34259

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000564

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000984

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2023

The c.1208T>C (p.L403P) alteration is located in exon 11 (coding exon 11) of the MTMR8 gene. This alteration results from a T to C substitution at nucleotide position 1208, causing the leucine (L) at amino acid position 403 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.72

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-5.6

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.74

MutPred

0.72

Loss of stability (P = 0.0257);

MVP

0.78

MPC

0.0077

ClinPred

0.98

GERP RS

3.4

Varity_R

0.98

gMVP

0.81

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over