Variant chr19-42326368-G-T 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_001271938.2(MEGF8):c.125G>T(p.Gly42Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000188 in 1,436,596 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: 0.000019 ( 0 hom. )

Consequence

MEGF8
NM_001271938.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.91

Variant links:

Genes affected

MEGF8 (HGNC:3233): (multiple EGF like domains 8) The protein encoded by this gene is a single-pass type I membrane protein of unknown function that contains several EGF-like domains, Kelch repeats, and PSI domains. Defects in this gene are a cause of Carpenter syndrome 2. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

MEGF8 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, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF8	NM_001271938.2 linkuse as main transcript	c.125G>T	p.Gly42Val	missense_variant	1/42	ENST00000251268.11	NP_001258867.1
MEGF8	NM_001410.3 linkuse as main transcript	c.125G>T	p.Gly42Val	missense_variant	1/41		NP_001401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF8	ENST00000251268.11 linkuse as main transcript	c.125G>T	p.Gly42Val	missense_variant	1/42	5	NM_001271938.2	ENSP00000251268	A2	Q7Z7M0-1
MEGF8	ENST00000334370.8 linkuse as main transcript	c.125G>T	p.Gly42Val	missense_variant	1/41	1		ENSP00000334219	P2	Q7Z7M0-2
MEGF8	ENST00000378073.5 linkuse as main transcript	c.-6961G>T		5_prime_UTR_variant	1/41	5		ENSP00000367313

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000188

AC:

AN:

1436596

Hom.:

Cov.:

AF XY:

0.0000112

AC XY:

AN XY:

714770

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000227

Gnomad4 OTH exome

AF:

0.0000337

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2022

The c.125G>T (p.G42V) alteration is located in exon 1 (coding exon 1) of the MEGF8 gene. This alteration results from a G to T substitution at nucleotide position 125, causing the glycine (G) at amino acid position 42 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

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

.;D

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.51

MutationAssessor

Pathogenic

3.1

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0040

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.98

D;.

Vest4

0.60

MutPred

0.95

Loss of disorder (P = 0.1216);Loss of disorder (P = 0.1216);

MVP

0.71

MPC

1.3

ClinPred

0.99

GERP RS

5.6

Varity_R

0.87

gMVP

0.86

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