16-84480705-T-C

Position:

• chr16-84480705-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020947.4(MEAK7):​c.1081A>G​(p.Met361Val) 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: MEAK7 NM_020947.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51

Genes affected

MEAK7 (HGNC:29325): (MTOR associated protein, eak-7 homolog) Involved in several processes, including TOR signaling; positive regulation of protein localization to lysosome; and response to insulin. Located in cytosol; lysosomal membrane; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEAK7	NM_020947.4	c.1081A>G	p.Met361Val	missense_variant	7/8	ENST00000343629.11	NP_065998.3
MEAK7	XM_005256075.3	c.1081A>G	p.Met361Val	missense_variant	8/9		XP_005256132.1
MEAK7	XM_017023511.2	c.1081A>G	p.Met361Val	missense_variant	7/8		XP_016879000.1
MEAK7	XM_047434410.1	c.1081A>G	p.Met361Val	missense_variant	7/8		XP_047290366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEAK7	ENST00000343629.11	c.1081A>G	p.Met361Val	missense_variant	7/8	1	NM_020947.4	ENSP00000343635	P1
MEAK7	ENST00000566995.5	c.*495A>G		3_prime_UTR_variant, NMD_transcript_variant	8/9	5		ENSP00000454265
MEAK7	ENST00000570036.5	c.*1136A>G		3_prime_UTR_variant, NMD_transcript_variant	8/9	2		ENSP00000455332

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

May 14, 2024

The c.1081A>G (p.M361V) alteration is located in exon 7 (coding exon 6) of the TLDC1 gene. This alteration results from a A to G substitution at nucleotide position 1081, causing the methionine (M) at amino acid position 361 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	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.88
MutPred		0.62		Gain of catalytic residue at M361 (P = 0.0116);
MVP		0.36
MPC		0.0060
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.87
gMVP		0.62

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: chr16-84514311;