rs141582110

Positions:

• chr19-42349479-ATCAC-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001271938.2(MEGF8):​c.2299-15_2299-12del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00469 in 1,604,856 control chromosomes in the GnomAD database, including 46 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (44 hom.)
• Consequence: MEGF8 NM_001271938.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.349

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 -16 ACMG points.

• BP6: Variant 19-42349479-ATCAC-A is Benign according to our data. Variant chr19-42349479-ATCAC-A is described in ClinVar as [Likely_benign]. Clinvar id is 446027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00317 (482/152060) while in subpopulation SAS AF= 0.0145 (70/4820). AF 95% confidence interval is 0.0118. There are 2 homozygotes in gnomad4. There are 258 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2	c.2299-15_2299-12del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000251268.11
MEGF8	NM_001410.3	c.2098-15_2098-12del		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11	c.2299-15_2299-12del		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001271938.2	A2
MEGF8	ENST00000334370.8	c.2098-15_2098-12del		splice_polypyrimidine_tract_variant, intron_variant		1		P2
MEGF8	ENST00000378073.5	c.-4787-15_-4787-12del		splice_polypyrimidine_tract_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00318 AC: 483 AN: 151944 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000629

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.00688

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00406

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00538 AC: 1296 AN: 240788 Hom.: 15 AF XY: 0.00591 AC XY: 772 AN XY: 130726

Gnomad AFR exome AF: 0.000515

Gnomad AMR exome AF: 0.00115

Gnomad ASJ exome AF: 0.00114

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.0135

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.00547

Gnomad OTH exome AF: 0.00696

GnomAD4 exome AF: 0.00485 AC: 7050 AN: 1452796 Hom.: 44 AF XY: 0.00522 AC XY: 3766 AN XY: 721830

Gnomad4 AFR exome AF: 0.000661

Gnomad4 AMR exome AF: 0.00115

Gnomad4 ASJ exome AF: 0.000971

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.0139

Gnomad4 FIN exome AF: 0.0107

Gnomad4 NFE exome AF: 0.00438

Gnomad4 OTH exome AF: 0.00553

GnomAD4 genome AF: 0.00317 AC: 482 AN: 152060 Hom.: 2 Cov.: 32 AF XY: 0.00347 AC XY: 258 AN XY: 74336

Gnomad4 AFR AF: 0.000627

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.00688

Gnomad4 NFE AF: 0.00406

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00364 Hom.: 0

Bravo AF: 0.00229

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 28, 2017	- -

MEGF8-related Carpenter syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

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: rs141582110; hg19: chr19-42853631;