rs150607375

chr19-42358892-C-Gchr19-42358892-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001271938.2(MEGF8):c.5281C>G(p.Leu1761Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000583 in 1,611,558 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1761L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00044 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00060 (1 hom.)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.473

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019727409).
• BP6: Variant 19-42358892-C-G is Benign according to our data. Variant chr19-42358892-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 473334.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000441 (67/151960) while in subpopulation NFE AF= 0.000941 (64/67990). AF 95% confidence interval is 0.000756. There are 1 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2	c.5281C>G	p.Leu1761Val	missense_variant	30/42	ENST00000251268.11
MEGF8	NM_001410.3	c.5080C>G	p.Leu1694Val	missense_variant	29/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11	c.5281C>G	p.Leu1761Val	missense_variant	30/42	5	NM_001271938.2	A2
MEGF8	ENST00000334370.8	c.5080C>G	p.Leu1694Val	missense_variant	29/41	1		P2
MEGF8	ENST00000378073.5	c.-1805C>G		5_prime_UTR_variant	30/41	5

Frequencies

GnomAD3 genomes AF: 0.000441 AC: 67 AN: 151960 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000941

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000463 AC: 114 AN: 246420 Hom.: 0 AF XY: 0.000465 AC XY: 62 AN XY: 133356

Gnomad AFR exome AF: 0.0000634

Gnomad AMR exome AF: 0.000176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000908

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000597 AC: 872 AN: 1459598 Hom.: 1 Cov.: 32 AF XY: 0.000637 AC XY: 462 AN XY: 725806

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000158

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.000394

Gnomad4 NFE exome AF: 0.000734

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000441 AC: 67 AN: 151960 Hom.: 1 Cov.: 31 AF XY: 0.000418 AC XY: 31 AN XY: 74216

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000539 Hom.: 1

Bravo AF: 0.000393

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000577 AC: 70

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.5080C>G (p.L1694V) alteration is located in exon 29 (coding exon 29) of the MEGF8 gene. This alteration results from a C to G substitution at nucleotide position 5080, causing the leucine (L) at amino acid position 1694 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

MEGF8-related Carpenter syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 03, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.10
Dann	Benign	0.25
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.020	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.30	N;N
REVEL	Benign	0.0010
Sift	Benign	0.17	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.0	B;B
Vest4		0.12
MVP		0.12
MPC		0.033
ClinPred		0.022	T
GERP RS		-5.1
Varity_R		0.034
gMVP		0.23

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: rs150607375; hg19: chr19-42863044;