8-17304461-G-C

Position:

• chr8-17304461-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004686.5(MTMR7):​c.1411C>G​(p.Leu471Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTMR7 NM_004686.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0960

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16905704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTMR7	NM_004686.5	c.1411C>G	p.Leu471Val	missense_variant	12/14	ENST00000180173.10	NP_004677.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTMR7	ENST00000180173.10	c.1411C>G	p.Leu471Val	missense_variant	12/14	1	NM_004686.5	ENSP00000180173.4
MTMR7	ENST00000521857.5	c.1411C>G	p.Leu471Val	missense_variant	12/13	5		ENSP00000429733.1
MTMR7	ENST00000519590.5	n.423C>G		non_coding_transcript_exon_variant	3/4	4
MTMR7	ENST00000519763.1	n.547C>G		non_coding_transcript_exon_variant	5/5	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2023

The c.1411C>G (p.L471V) alteration is located in exon 12 (coding exon 12) of the MTMR7 gene. This alteration results from a C to G substitution at nucleotide position 1411, causing the leucine (L) at amino acid position 471 to be replaced by a valine (V). 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	Benign	0.069
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	3.5
DANN	Benign	0.96
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.56	N;N
REVEL	Benign	0.24
Sift	Benign	0.42	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.0	B;B
Vest4		0.23
MutPred		0.25		Gain of MoRF binding (P = 0.0899);Gain of MoRF binding (P = 0.0899);
MVP		0.65
MPC		0.019
ClinPred		0.052	T
GERP RS		-3.6
Varity_R		0.047
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-17161970;