rs143955737

chr19-42334003-G-A

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003003
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0840

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2	c.352-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000251268.11
MEGF8	NM_001410.3	c.352-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11	c.352-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001271938.2	A2
MEGF8	ENST00000334370.8	c.352-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P2
MEGF8	ENST00000378073.5	c.-6734-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5

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

GnomAD3 exomes AF: 0.0140 AC: 3445 AN: 245690 Hom.: 183 AF XY: 0.0105 AC XY: 1404 AN XY: 133330

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 SAS exome AF: 0.0000662

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

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.0891

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000582

Gnomad4 FIN exome AF: 0.00227

Gnomad4 NFE exome AF: 0.000143

Gnomad4 OTH exome AF: 0.00274

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

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.0339

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00332

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 16, 2019

- -

MEGF8-related Carpenter syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.15
Dann	Benign	0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs143955737; hg19: chr19-42838155;