Variant 19-42356864-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001271938.2(MEGF8):c.4713C>T(p.Ala1571Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00955 in 1,589,726 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 15 hom., cov: 32)

Exomes 𝑓: 0.0098 ( 118 hom. )

Consequence

MEGF8
NM_001271938.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.88

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 19-42356864-C-T is Benign according to our data. Variant chr19-42356864-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 473333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.88 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00699 (1064/152326) while in subpopulation SAS AF= 0.0337 (163/4834). AF 95% confidence interval is 0.0295. There are 15 homozygotes in gnomad4. There are 551 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF8	NM_001271938.2 linkuse as main transcript	c.4713C>T	p.Ala1571Ala	synonymous_variant	27/42	ENST00000251268.11	NP_001258867.1	Q7Z7M0-1
MEGF8	NM_001410.3 linkuse as main transcript	c.4512C>T	p.Ala1504Ala	synonymous_variant	26/41		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.4713C>T	p.Ala1571Ala	synonymous_variant	27/42	5	NM_001271938.2	ENSP00000251268.5	Q7Z7M0-1
MEGF8	ENST00000334370.8 linkuse as main transcript	c.4512C>T	p.Ala1504Ala	synonymous_variant	26/41	1		ENSP00000334219.4	Q7Z7M0-2
MEGF8	ENST00000378073.5 linkuse as main transcript	c.-2373C>T		5_prime_UTR_premature_start_codon_gain_variant	27/41	5		ENSP00000367313.4	F5GZG7
MEGF8	ENST00000378073.5 linkuse as main transcript	c.-2373C>T		5_prime_UTR_variant	27/41	5		ENSP00000367313.4	F5GZG7

Frequencies

GnomAD3 genomes

AF:

0.00702

AC:

1069

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00844

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0347

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00851

Gnomad OTH

AF:

0.0125

GnomAD3 exomes

AF:

0.0102

AC:

2159

AN:

212094

Hom.:

AF XY:

0.0120

AC XY:

1369

AN XY:

114272

show subpopulations

Gnomad AFR exome

AF:

0.00102

Gnomad AMR exome

AF:

0.00639

Gnomad ASJ exome

AF:

0.0169

Gnomad EAS exome

AF:

0.0000635

Gnomad SAS exome

AF:

0.0335

Gnomad FIN exome

AF:

0.00314

Gnomad NFE exome

AF:

0.00867

Gnomad OTH exome

AF:

0.00938

GnomAD4 exome

AF:

0.00982

AC:

14118

AN:

1437400

Hom.:

118

Cov.:

AF XY:

0.0107

AC XY:

7653

AN XY:

712720

show subpopulations

Gnomad4 AFR exome

AF:

0.00115

Gnomad4 AMR exome

AF:

0.00711

Gnomad4 ASJ exome

AF:

0.0181

Gnomad4 EAS exome

AF:

0.0000521

Gnomad4 SAS exome

AF:

0.0335

Gnomad4 FIN exome

AF:

0.00270

Gnomad4 NFE exome

AF:

0.00873

Gnomad4 OTH exome

AF:

0.0108

GnomAD4 genome

AF:

0.00699

AC:

1064

AN:

152326

Hom.:

Cov.:

AF XY:

0.00740

AC XY:

551

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00173

Gnomad4 AMR

AF:

0.00843

Gnomad4 ASJ

AF:

0.0161

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0337

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.00853

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.00650

Hom.:

Bravo

AF:

0.00635

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

MEGF8-related Carpenter syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

6.8

DANN

Benign

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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