rs73033442

chr19-42370743-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_001271938.2(MEGF8):c.7048G>A(p.Val2350Met) variant causes a missense change. The variant allele was found at a frequency of 0.000853 in 1,585,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00088 (0 hom.)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.63

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.019539297).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000555 (84/151320) while in subpopulation NFE AF= 0.0009 (61/67742). AF 95% confidence interval is 0.000719. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2	c.7048G>A	p.Val2350Met	missense_variant	40/42	ENST00000251268.11
MEGF8	NM_001410.3	c.6847G>A	p.Val2283Met	missense_variant	39/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11	c.7048G>A	p.Val2350Met	missense_variant	40/42	5	NM_001271938.2	A2

Frequencies

GnomAD3 genomes AF: 0.000556 AC: 84 AN: 151202 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000243

Gnomad AMI AF: 0.00773

Gnomad AMR AF: 0.000265

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000900

Gnomad OTH AF: 0.000484

GnomAD3 exomes AF: 0.000477 AC: 99 AN: 207336 Hom.: 0 AF XY: 0.000469 AC XY: 52 AN XY: 110812

Gnomad AFR exome AF: 0.000395

Gnomad AMR exome AF: 0.000511

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000850

Gnomad OTH exome AF: 0.000374

GnomAD4 exome AF: 0.000885 AC: 1269 AN: 1434242 Hom.: 0 Cov.: 31 AF XY: 0.000853 AC XY: 606 AN XY: 710754

Gnomad4 AFR exome AF: 0.000182

Gnomad4 AMR exome AF: 0.000397

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: 0.00109

Gnomad4 OTH exome AF: 0.000824

GnomAD4 genome AF: 0.000555 AC: 84 AN: 151320 Hom.: 0 Cov.: 27 AF XY: 0.000568 AC XY: 42 AN XY: 73920

Gnomad4 AFR AF: 0.000242

Gnomad4 AMR AF: 0.000264

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000210

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000900

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000844 Hom.: 0

Bravo AF: 0.000563

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00175 AC: 15

ExAC AF: 0.000339 AC: 41

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 2019	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2019	- -

MEGF8-related Carpenter syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 21, 2022

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2283 of the MEGF8 protein (p.Val2283Met). This variant is present in population databases (rs73033442, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MEGF8-related conditions. ClinVar contains an entry for this variant (Variation ID: 569417). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	16
Dann	Benign	0.85
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Benign	-0.61	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.5	N;N;.
REVEL	Benign	0.12
Sift	Benign	0.11	T;T;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;B;.
Vest4		0.28
MVP		0.39
MPC		0.59
ClinPred		0.020	T
GERP RS		2.1
Varity_R		0.10
gMVP		0.50

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

Other links and lift over

dbSNP: rs73033442; hg19: chr19-42874895;