NM_001271938.2:c.352-4G>A

Variant names:

• chr19-42334003-G-A
• rs143955737
• NM_001271938.2:c.352-4G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001271938.2(MEGF8):​c.352-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,612,054 control chromosomes in the GnomAD database, including 231 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (213 hom.)
• Consequence: MEGF8 NM_001271938.2 splice_region, intron
• Scores: Splicing: ADA: 0.0003003
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0840
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-42334003-G-A is Benign according to our data. Variant chr19-42334003-G-A is described in ClinVar as Benign. ClinVar VariationId is 473327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0868 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	NM_001271938.2	MANE Select	c.352-4G>A		splice_region intron	N/A	NP_001258867.1
	MEGF8	NM_001410.3		c.352-4G>A		splice_region intron	N/A	NP_001401.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	ENST00000251268.11	TSL:5 MANE Select	c.352-4G>A		splice_region intron	N/A	ENSP00000251268.5
	MEGF8	ENST00000334370.8	TSL:1	c.352-4G>A		splice_region intron	N/A	ENSP00000334219.4
	MEGF8	ENST00000378073.5	TSL:5	c.-6734-4G>A		splice_region intron	N/A	ENSP00000367313.4

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 609 AN: 152166 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0338

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.0140 AC: 3445 AN: 245690 AF XY: 0.0105

Gnomad AFR exome AF: 0.000595

Gnomad AMR exome AF: 0.0963

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00206

Gnomad NFE exome AF: 0.000458

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.00302 AC: 4411 AN: 1459768 Hom.: 213 Cov.: 31 AF XY: 0.00256 AC XY: 1856 AN XY: 726018

African (AFR) AF: 0.000389 AC: 13 AN: 33454

American (AMR) AF: 0.0891 AC: 3944 AN: 44270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39658

South Asian (SAS) AF: 0.0000582 AC: 5 AN: 85910

European-Finnish (FIN) AF: 0.00227 AC: 121 AN: 53240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000143 AC: 159 AN: 1111120

Other (OTH) AF: 0.00274 AC: 165 AN: 60298

GnomAD4 genome AF: 0.00402 AC: 612 AN: 152286 Hom.: 18 Cov.: 32 AF XY: 0.00414 AC XY: 308 AN XY: 74454

African (AFR) AF: 0.000746 AC: 31 AN: 41558

American (AMR) AF: 0.0339 AC: 519 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68016

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00145 Hom.: 6

Bravo AF: 0.00916

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Apr 16, 2019

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEGF8-related Carpenter syndrome Benign:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.15
DANN	Benign	0.53
PhyloP100		-0.084
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00030
dbscSNV1_RF	Benign	0.020
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: rs143955737; hg19: chr19-42838155; COSMIC: COSV109408174;