17-58495063-G-T

Position:

• chr17-58495063-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001378067.1(MTMR4):​c.3121C>A​(p.Gln1041Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTMR4 NM_001378067.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.36

Genes affected

MTMR4 (HGNC:7452): (myotubularin related protein 4) Enables protein phosphatase binding activity. Involved in regulation of phosphatidylinositol dephosphorylation. Located in endosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTMR4	NM_001378067.1	c.3121C>A	p.Gln1041Lys	missense_variant	15/18	ENST00000682306.1	NP_001364996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTMR4	ENST00000682306.1	c.3121C>A	p.Gln1041Lys	missense_variant	15/18		NM_001378067.1	ENSP00000507664.1
MTMR4	ENST00000323456.9	c.3079C>A	p.Gln1027Lys	missense_variant	16/19	1		ENSP00000325285.5
MTMR4	ENST00000579925.5	c.2908C>A	p.Gln970Lys	missense_variant	15/18	5		ENSP00000464067.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Mar 25, 2024

The c.3079C>A (p.Q1027K) alteration is located in exon 16 (coding exon 15) of the MTMR4 gene. This alteration results from a C to A substitution at nucleotide position 3079, causing the glutamine (Q) at amino acid position 1027 to be replaced by a lysine (K). 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	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.4	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.6	.;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0030	.;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	.;D
Vest4		0.75
MutPred		0.35		.;Gain of ubiquitination at Q1027 (P = 0.0247);
MVP		0.63
MPC		1.1
ClinPred		0.94	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr17-56572424; COSMIC: COSV60200816; COSMIC: COSV60200816;