rs372990477

chr19-42336126-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BS1_Supporting

The NM_001271938.2(MEGF8):c.1024G>A(p.Val342Met) variant causes a missense change. The variant allele was found at a frequency of 0.000547 in 1,608,380 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (1 hom.)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.29

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28805605).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000289 (44/152274) while in subpopulation NFE AF= 0.000514 (35/68040). AF 95% confidence interval is 0.000379. There are 0 homozygotes in gnomad4. There are 14 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.1024G>A	p.Val342Met	missense_variant	6/42	ENST00000251268.11
MEGF8	NM_001410.3	c.1024G>A	p.Val342Met	missense_variant	6/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11	c.1024G>A	p.Val342Met	missense_variant	6/42	5	NM_001271938.2	A2
MEGF8	ENST00000334370.8	c.1024G>A	p.Val342Met	missense_variant	6/41	1		P2
MEGF8	ENST00000378073.5	c.-6062G>A		5_prime_UTR_variant	6/41	5

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152274 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000221 AC: 54 AN: 244254 Hom.: 0 AF XY: 0.000248 AC XY: 33 AN XY: 133150

Gnomad AFR exome AF: 0.000197

Gnomad AMR exome AF: 0.0000583

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: 0.000430

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000573 AC: 835 AN: 1456106 Hom.: 1 Cov.: 32 AF XY: 0.000573 AC XY: 415 AN XY: 724378

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000672

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: 0.000726

Gnomad4 OTH exome AF: 0.000332

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74396

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000460 Hom.: 0

Bravo AF: 0.000264

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000718 AC: 6

ExAC AF: 0.000215 AC: 26

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MEGF8-related Carpenter syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 07, 2022

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 342 of the MEGF8 protein (p.Val342Met). This variant is present in population databases (rs372990477, gnomAD 0.04%). 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: 575246). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 04, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.055	T;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.39
MVP		0.65
MPC		0.82
ClinPred		0.11	T
GERP RS		4.4
Varity_R		0.076
gMVP		0.83

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: rs372990477; hg19: chr19-42840278;