Variant rs143955737 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001271938.2(MEGF8):c.352-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,612,054 control chromosomes in the GnomAD database, including 231 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 18 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 213 hom. )

Consequence

MEGF8
NM_001271938.2 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0003003

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0840

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 19-42334003-G-A is Benign according to our data. Variant chr19-42334003-G-A is described in ClinVar as [Benign]. Clinvar id is 473327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF8	NM_001271938.2 linkuse as main transcript	c.352-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000251268.11	NP_001258867.1
MEGF8	NM_001410.3 linkuse as main transcript	c.352-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001401.2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
MEGF8	ENST00000251268.11 linkuse as main transcript	c.352-4G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	5	NM_001271938.2	ENSP00000251268	A2	Q7Z7M0-1
MEGF8	ENST00000334370.8 linkuse as main transcript	c.352-4G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1		ENSP00000334219	P2	Q7Z7M0-2
MEGF8	ENST00000378073.5 linkuse as main transcript	c.-6734-4G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	5		ENSP00000367313

Frequencies

GnomAD3 genomes

AF:

0.00400

AC:

609

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0338

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00245

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.0140

AC:

3445

AN:

245690

Hom.:

183

AF XY:

0.0105

AC XY:

1404

AN XY:

133330

show subpopulations

Gnomad AFR exome

AF:

0.000595

Gnomad AMR exome

AF:

0.0963

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000168

Gnomad SAS exome

AF:

0.0000662

Gnomad FIN exome

AF:

0.00206

Gnomad NFE exome

AF:

0.000458

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.00302

AC:

4411

AN:

1459768

Hom.:

213

Cov.:

AF XY:

0.00256

AC XY:

1856

AN XY:

726018

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

Gnomad4 AMR exome

AF:

0.0891

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000582

Gnomad4 FIN exome

AF:

0.00227

Gnomad4 NFE exome

AF:

0.000143

Gnomad4 OTH exome

AF:

0.00274

GnomAD4 genome

AF:

0.00402

AC:

612

AN:

152286

Hom.:

Cov.:

AF XY:

0.00414

AC XY:

308

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.0339

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00245

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00145

Hom.:

Bravo

AF:

0.00916

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 16, 2019

- -

MEGF8-related Carpenter syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.15

DANN

Benign

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00030

dbscSNV1_RF

Benign

0.020

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