rs537269414

Variant names:

• chr19-42376704-A-G
• rs537269414
• NM_001271938.2:c.8467A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001271938.2(MEGF8):​c.8467A>G​(p.Ser2823Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00462 in 152,318 control chromosomes in the GnomAD database, including 8 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 Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0046 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.19
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
• Carpenter syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046291947).
• BP6: Variant 19-42376704-A-G is Benign according to our data. Variant chr19-42376704-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00462 (704/152318) while in subpopulation AFR AF = 0.016 (666/41572). AF 95% confidence interval is 0.015. There are 8 homozygotes in GnomAd4. There are 340 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

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.8467A>G	p.Ser2823Gly	missense	Exon 42 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.8266A>G	p.Ser2756Gly	missense	Exon 41 of 41	NP_001401.2	Q7Z7M0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	ENST00000251268.11	TSL:5 MANE Select	c.8467A>G	p.Ser2823Gly	missense	Exon 42 of 42	ENSP00000251268.5	Q7Z7M0-1
	MEGF8	ENST00000334370.8	TSL:1	c.8266A>G	p.Ser2756Gly	missense	Exon 41 of 41	ENSP00000334219.4	Q7Z7M0-2
	MEGF8	ENST00000593647.1	TSL:1	c.*1056A>G		3_prime_UTR	Exon 4 of 4	ENSP00000470620.1	M0QZL2

Frequencies

GnomAD3 genomes AF: 0.00461 AC: 701 AN: 152202 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

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: 0.00

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00110 AC: 130 AN: 118380 AF XY: 0.00106

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.000892

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000218

Gnomad OTH exome AF: 0.000281

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000412 AC: 559 AN: 1355198 Hom.: 3 Cov.: 31 AF XY: 0.000380 AC XY: 252 AN XY: 663660

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0140 AC: 439 AN: 31336

American (AMR) AF: 0.000829 AC: 28 AN: 33768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22584

East Asian (EAS) AF: 0.00 AC: 0 AN: 35824

South Asian (SAS) AF: 0.00 AC: 0 AN: 73154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37338

Middle Eastern (MID) AF: 0.000221 AC: 1 AN: 4516

European-Non Finnish (NFE) AF: 0.0000245 AC: 26 AN: 1060288

Other (OTH) AF: 0.00115 AC: 65 AN: 56390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00462 AC: 704 AN: 152318 Hom.: 8 Cov.: 32 AF XY: 0.00456 AC XY: 340 AN XY: 74496

African (AFR) AF: 0.0160 AC: 666 AN: 41572

American (AMR) AF: 0.00189 AC: 29 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00190 Hom.: 2

Bravo AF: 0.00483

ExAC AF: 0.000354 AC: 39

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	MEGF8-related Carpenter syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.2
DANN	Benign	0.94
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.089
Sift	Benign	0.054	T
Sift4G	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.18
MPC		0.49
ClinPred		0.0046	T
GERP RS		2.4
Varity_R		0.046
gMVP		0.34
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs537269414; hg19: chr19-42880856; COSMIC: COSV52074632; COSMIC: COSV52074632;