NM_001271938.2:c.919G>A

Variant names:

• chr19-42336021-G-A
• rs201180083
• NM_001271938.2:c.919G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001271938.2(MEGF8):​c.919G>A​(p.Val307Met) variant causes a missense change. The variant allele was found at a frequency of 0.000129 in 1,560,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.10
• Publications: 2 publications found

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]

MEGF8 Gene-Disease associations (from GenCC):

• MEGF8-related Carpenter syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• Carpenter syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014833897).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000584 (89/152370) while in subpopulation AFR AF = 0.00204 (85/41584). AF 95% confidence interval is 0.00169. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271938.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	NM_001271938.2	MANE Select	c.919G>A	p.Val307Met	missense	Exon 6 of 42	NP_001258867.1
	MEGF8	NM_001410.3		c.919G>A	p.Val307Met	missense	Exon 6 of 41	NP_001401.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	ENST00000251268.11	TSL:5 MANE Select	c.919G>A	p.Val307Met	missense	Exon 6 of 42	ENSP00000251268.5
	MEGF8	ENST00000334370.8	TSL:1	c.919G>A	p.Val307Met	missense	Exon 6 of 41	ENSP00000334219.4
	MEGF8	ENST00000378073.5	TSL:5	c.-6167G>A		5_prime_UTR_premature_start_codon_gain	Exon 6 of 41	ENSP00000367313.4

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00205

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: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000146 AC: 25 AN: 171658 AF XY: 0.000118

Gnomad AFR exome AF: 0.00230

Gnomad AMR exome AF: 0.0000374

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000796 AC: 112 AN: 1407654 Hom.: 0 Cov.: 32 AF XY: 0.0000689 AC XY: 48 AN XY: 696654

African (AFR) AF: 0.00220 AC: 71 AN: 32282

American (AMR) AF: 0.0000531 AC: 2 AN: 37630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25354

East Asian (EAS) AF: 0.00 AC: 0 AN: 36828

South Asian (SAS) AF: 0.00 AC: 0 AN: 81062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.0000257 AC: 28 AN: 1088348

Other (OTH) AF: 0.000188 AC: 11 AN: 58480

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152370 Hom.: 0 Cov.: 33 AF XY: 0.000550 AC XY: 41 AN XY: 74518

African (AFR) AF: 0.00204 AC: 85 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68044

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000124 Hom.: 0

Bravo AF: 0.000567

ESP6500AA AF: 0.00102 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000126 AC: 15

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	MEGF8-related Carpenter syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.094	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.15
Sift	Benign	0.063	T
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.43
MVP		0.15
MPC		0.39
ClinPred		0.059	T
GERP RS		3.6
Varity_R		0.053
gMVP		0.35
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201180083; hg19: chr19-42840173;