dbSNP rs115536529: MEGF8:p.Leu119Leu (chr19-42334012-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

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

The NM_001271938.2(MEGF8):c.357G>A(p.Leu119Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,613,322 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 11 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 8 hom. )

Consequence

MEGF8
NM_001271938.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.12

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=-0.45).

BP6

Variant 19-42334012-G-A is Benign according to our data. Variant chr19-42334012-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 473328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.12 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00572 (871/152260) while in subpopulation AFR AF= 0.0195 (811/41546). AF 95% confidence interval is 0.0184. There are 11 homozygotes in gnomad4. There are 391 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF8	NM_001271938.2 link	c.357G>A	p.Leu119Leu	synonymous_variant	Exon 3 of 42	ENST00000251268.11	NP_001258867.1	Q7Z7M0-1
MEGF8	NM_001410.3 link	c.357G>A	p.Leu119Leu	synonymous_variant	Exon 3 of 41		NP_001401.2	Q7Z7M0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MEGF8	ENST00000251268.11 link	c.357G>A	p.Leu119Leu	synonymous_variant	Exon 3 of 42	5	NM_001271938.2	ENSP00000251268.5	Q7Z7M0-1
MEGF8	ENST00000334370.8 link	c.357G>A	p.Leu119Leu	synonymous_variant	Exon 3 of 41	1		ENSP00000334219.4	Q7Z7M0-2
MEGF8	ENST00000378073 link	c.-6729G>A		5_prime_UTR_variant	Exon 3 of 41	5		ENSP00000367313.4	F5GZG7

Frequencies

GnomAD3 genomes

AF:

0.00570

AC:

867

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0195

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00141

AC:

349

AN:

247840

Hom.:

AF XY:

0.00104

AC XY:

140

AN XY:

134508

show subpopulations

Gnomad AFR exome

AF:

0.0197

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000562

AC:

821

AN:

1461062

Hom.:

Cov.:

AF XY:

0.000477

AC XY:

347

AN XY:

726762

show subpopulations

Gnomad4 AFR exome

AF:

0.0201

Gnomad4 AMR exome

AF:

0.00137

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00131

GnomAD4 genome

AF:

0.00572

AC:

871

AN:

152260

Hom.:

Cov.:

AF XY:

0.00525

AC XY:

391

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0195

Gnomad4 AMR

AF:

0.00301

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00254

Hom.:

Bravo

AF:

0.00643

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

MEGF8-related Carpenter syndrome

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Apr 07, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

9.7

DANN

Benign

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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