8-17302209-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_004686.5(MTMR7):c.1565T>C(p.Met522Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00277 in 1,614,098 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (12 hom.)
• Consequence: MTMR7 NM_004686.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.11

Genes affected

MTMR7 (HGNC:7454): (myotubularin related protein 7) This gene encodes a member of the myotubularin family of tyrosine/dual-specificity phosphatases. The encoded protein is characterized by four distinct domains that are conserved among all members of the myotubularin family: the glucosyltransferase, Rab-like GTPase activator and myotubularins domain, the Rac-induced recruitment domain, the protein tyrosine phosphatases and dual-specificity phosphatases domain and the suppressor of variegation 3-9, enhancer-of-zeste, and trithorax interaction domain. This protein dephosphorylates the target substrates phosphatidylinositol 3-phosphate and inositol 1,3-bisphosphate. A pseudogene of this gene is found on chromosome 5. [provided by RefSeq, Mar 2009]

VPS37A (HGNC:24928): (VPS37A subunit of ESCRT-I) This gene belongs to the VPS37 family, and encodes a component of the ESCRT-I (endosomal sorting complex required for transport I) protein complex, required for the sorting of ubiquitinated transmembrane proteins into internal vesicles of multivesicular bodies. Expression of this gene is downregulated in hepatocellular carcinoma, and mutations in this gene are associated with autosomal recessive spastic paraplegia-53. A related pseudogene has been identified on chromosome 5. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011514902).
• BP6: Variant 8-17302209-A-G is Benign according to our data. Variant chr8-17302209-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3042663.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTMR7	NM_004686.5	c.1565T>C	p.Met522Thr	missense_variant	13/14	ENST00000180173.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTMR7	ENST00000180173.10	c.1565T>C	p.Met522Thr	missense_variant	13/14	1	NM_004686.5	P1
MTMR7	ENST00000521857.5	c.1565T>C	p.Met522Thr	missense_variant	13/13	5
MTMR7	ENST00000519590.5	n.577T>C		non_coding_transcript_exon_variant	4/4	4
VPS37A	ENST00000519515.1	n.53-5A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 350 AN: 152176 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00461

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00359

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00192 AC: 482 AN: 251174 Hom.: 0 AF XY: 0.00181 AC XY: 246 AN XY: 135742

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.00351

Gnomad NFE exome AF: 0.00285

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00282 AC: 4115 AN: 1461804 Hom.: 12 Cov.: 30 AF XY: 0.00278 AC XY: 2025 AN XY: 727204

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00132

Gnomad4 FIN exome AF: 0.00346

Gnomad4 NFE exome AF: 0.00323

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.00230 AC: 350 AN: 152294 Hom.: 1 Cov.: 32 AF XY: 0.00244 AC XY: 182 AN XY: 74474

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00461

Gnomad4 NFE AF: 0.00359

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00282 Hom.: 4

Bravo AF: 0.00184

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00197 AC: 239

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MTMR7-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	18
Dann	Benign	0.95
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.034
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.11
Sift	Benign	0.12	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.080	B;B
Vest4		0.73
MVP		0.71
MPC		0.020
ClinPred		0.015	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.44

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

Other links and lift over

dbSNP: rs117739013; hg19: chr8-17159718; COSMIC: COSV99073676; COSMIC: COSV99073676;