19-42333679-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_001271938.2(MEGF8):c.262G>A(p.Val88Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000446 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.83

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000217 (33/152208) while in subpopulation AFR AF= 0.000676 (28/41438). AF 95% confidence interval is 0.000479. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 32. 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.262G>A	p.Val88Met	missense_variant	2/42	ENST00000251268.11
MEGF8	NM_001410.3	c.262G>A	p.Val88Met	missense_variant	2/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11	c.262G>A	p.Val88Met	missense_variant	2/42	5	NM_001271938.2	A2
MEGF8	ENST00000334370.8	c.262G>A	p.Val88Met	missense_variant	2/41	1		P2
MEGF8	ENST00000378073.5	c.-6824G>A		5_prime_UTR_variant	2/41	5

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000722 AC: 18 AN: 249172 Hom.: 0 AF XY: 0.0000444 AC XY: 6 AN XY: 135192

Gnomad AFR exome AF: 0.000581

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461656 Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17 AN XY: 727116

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000134

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74356

Gnomad4 AFR AF: 0.000676

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000161 Hom.: 0

Bravo AF: 0.000223

ESP6500AA AF: 0.000483 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000991 AC: 12

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Jul 01, 2019

This sequence change replaces valine with methionine at codon 88 of the MEGF8 protein (p.Val88Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs372955721, ExAC 0.08%). This variant has not been reported in the literature in individuals with MEGF8-related conditions. 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: "Probably 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

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Feb 19, 2024

PM3_Supporting, PP2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.66
MVP		0.80
MPC		1.2
ClinPred		0.30	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.54

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: rs372955721; hg19: chr19-42837831; COSMIC: COSV52074222;