Variant chr19-42357415-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001271938.2(MEGF8):c.4842C>T(p.Thr1614Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,613,256 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 21 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 40 hom. )

Consequence

MEGF8
NM_001271938.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.356

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 Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 19-42357415-C-T is Benign according to our data. Variant chr19-42357415-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 540557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.356 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0113 (1725/152240) while in subpopulation AFR AF= 0.0339 (1406/41530). AF 95% confidence interval is 0.0324. There are 21 homozygotes in gnomad4. There are 807 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF8	NM_001271938.2 linkuse as main transcript	c.4842C>T	p.Thr1614Thr	synonymous_variant	28/42	ENST00000251268.11	NP_001258867.1	Q7Z7M0-1
MEGF8	NM_001410.3 linkuse as main transcript	c.4641C>T	p.Thr1547Thr	synonymous_variant	27/41		NP_001401.2	Q7Z7M0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MEGF8	ENST00000251268.11 linkuse as main transcript	c.4842C>T	p.Thr1614Thr	synonymous_variant	28/42	5	NM_001271938.2	ENSP00000251268.5	Q7Z7M0-1
MEGF8	ENST00000334370.8 linkuse as main transcript	c.4641C>T	p.Thr1547Thr	synonymous_variant	27/41	1		ENSP00000334219.4	Q7Z7M0-2
MEGF8	ENST00000378073.5 linkuse as main transcript	c.-2244C>T		5_prime_UTR_premature_start_codon_gain_variant	28/41	5		ENSP00000367313.4	F5GZG7
MEGF8	ENST00000378073.5 linkuse as main transcript	c.-2244C>T		5_prime_UTR_variant	28/41	5		ENSP00000367313.4	F5GZG7

Frequencies

GnomAD3 genomes

AF:

0.0113

AC:

1724

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0339

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00975

Gnomad ASJ

AF:

0.00779

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00144

Gnomad OTH

AF:

0.0163

GnomAD3 exomes

AF:

0.00428

AC:

1070

AN:

249730

Hom.:

AF XY:

0.00366

AC XY:

495

AN XY:

135080

show subpopulations

Gnomad AFR exome

AF:

0.0362

Gnomad AMR exome

AF:

0.00570

Gnomad ASJ exome

AF:

0.00670

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00151

Gnomad OTH exome

AF:

0.00541

GnomAD4 exome

AF:

0.00228

AC:

3332

AN:

1461016

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

1565

AN XY:

726798

show subpopulations

Gnomad4 AFR exome

AF:

0.0360

Gnomad4 AMR exome

AF:

0.00611

Gnomad4 ASJ exome

AF:

0.00786

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.00106

Gnomad4 OTH exome

AF:

0.00590

GnomAD4 genome

AF:

0.0113

AC:

1725

AN:

152240

Hom.:

Cov.:

AF XY:

0.0108

AC XY:

807

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0339

Gnomad4 AMR

AF:

0.00974

Gnomad4 ASJ

AF:

0.00779

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00144

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.00619

Hom.:

Bravo

AF:

0.0134

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00234

EpiControl

AF:

0.00249

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2021	- -

MEGF8-related Carpenter syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.28

DANN

Benign

0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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