Variant 16-84480583-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_020947.4(MEAK7):c.1203C>G(p.Phe401Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

MEAK7
NM_020947.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.32

Variant links:

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]

MEAK7 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MEAK7	NM_020947.4 linkuse as main transcript	c.1203C>G	p.Phe401Leu	missense_variant	7/8	ENST00000343629.11	NP_065998.3
MEAK7	XM_005256075.3 linkuse as main transcript	c.1203C>G	p.Phe401Leu	missense_variant	8/9		XP_005256132.1
MEAK7	XM_017023511.2 linkuse as main transcript	c.1203C>G	p.Phe401Leu	missense_variant	7/8		XP_016879000.1
MEAK7	XM_047434410.1 linkuse as main transcript	c.1203C>G	p.Phe401Leu	missense_variant	7/8		XP_047290366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MEAK7	ENST00000343629.11 linkuse as main transcript	c.1203C>G	p.Phe401Leu	missense_variant	7/8	1	NM_020947.4	ENSP00000343635	P1
MEAK7	ENST00000566995.5 linkuse as main transcript	c.*617C>G		3_prime_UTR_variant, NMD_transcript_variant	8/9	5		ENSP00000454265
MEAK7	ENST00000570036.5 linkuse as main transcript	c.*1258C>G		3_prime_UTR_variant, NMD_transcript_variant	8/9	2		ENSP00000455332

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251184

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135750

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:

0.000359

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461750

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000659

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

Sep 13, 2023

The c.1203C>G (p.F401L) alteration is located in exon 7 (coding exon 6) of the TLDC1 gene. This alteration results from a C to G substitution at nucleotide position 1203, causing the phenylalanine (F) at amino acid position 401 to be replaced by a leucine (L). 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

0.99

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.75

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

-0.19

MutationAssessor

Pathogenic

3.9

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.7

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.92

MutPred

0.96

Loss of sheet (P = 0.1158);

MVP

0.33

MPC

0.0058

ClinPred

0.99

GERP RS

2.9

Varity_R

0.91

gMVP

0.84

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