chr19-42349650-A-G

Position:

• chr19-42349650-A-G

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.2450A>G​(p.His817Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000573 in 1,612,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (0 hom.)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.86

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=0.009564936).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000493 (75/152252) while in subpopulation SAS AF= 0.00228 (11/4832). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4. There are 35 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	Protein	UniProt
MEGF8	NM_001271938.2	c.2450A>G	p.His817Arg	missense_variant	14/42	ENST00000251268.11	NP_001258867.1
MEGF8	NM_001410.3	c.2249A>G	p.His750Arg	missense_variant	13/41		NP_001401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF8	ENST00000251268.11	c.2450A>G	p.His817Arg	missense_variant	14/42	5	NM_001271938.2	ENSP00000251268.5
MEGF8	ENST00000334370.8	c.2249A>G	p.His750Arg	missense_variant	13/41	1		ENSP00000334219.4
MEGF8	ENST00000378073.5	c.-4636A>G		5_prime_UTR_variant	14/41	5		ENSP00000367313.4

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000555 AC: 138 AN: 248504 Hom.: 0 AF XY: 0.000632 AC XY: 85 AN XY: 134538

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000611

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000582 AC: 849 AN: 1459812 Hom.: 0 Cov.: 32 AF XY: 0.000633 AC XY: 460 AN XY: 726248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00157

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000586

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74442

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000574

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000480 Hom.: 0

Bravo AF: 0.000431

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000577 AC: 70

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00107

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MEGF8-related Carpenter syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed missense c.2450A>G p.His817Arg variant in MEGF8 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.His817Arg variant has allele frequency 0.05% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. Multiple lines of computational evidence Polyphen - Possibly damaging, SIFT - Tolerated and Mutation Taster - Disease causing predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.His817Arg in MEGF8 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid His at position 817 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance VUS. In the absence of another reportable variant in MEGF8 gene, the molecular diagnosis is not confirmed. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 27, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 07, 2022	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 750 of the MEGF8 protein (p.His750Arg). This variant is present in population databases (rs151116615, gnomAD 0.2%), 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: 577904). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.2249A>G (p.H750R) alteration is located in exon 13 (coding exon 13) of the MEGF8 gene. This alteration results from a A to G substitution at nucleotide position 2249, causing the histidine (H) at amino acid position 750 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.10	.;T
Eigen	Benign	-0.074
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0096	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	.;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.069
Sift	Benign	0.17	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.56	P;B
Vest4		0.32
MVP		0.11
MPC		0.76
ClinPred		0.021	T
GERP RS		3.5
Varity_R		0.12
gMVP		0.49

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: rs151116615; hg19: chr19-42853802;