rs145886667

Positions:

• chr19-42370736-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001271938.2(MEGF8):​c.7041C>T​(p.Asp2347=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,588,454 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0021 (8 hom.)
• Consequence: MEGF8 NM_001271938.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.75

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 19-42370736-C-T is Benign according to our data. Variant chr19-42370736-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 473341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00172 (260/151206) while in subpopulation NFE AF= 0.00167 (113/67780). AF 95% confidence interval is 0.00142. There are 0 homozygotes in gnomad4. There are 147 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2	c.7041C>T	p.Asp2347=	synonymous_variant	40/42	ENST00000251268.11
MEGF8	NM_001410.3	c.6840C>T	p.Asp2280=	synonymous_variant	39/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11	c.7041C>T	p.Asp2347=	synonymous_variant	40/42	5	NM_001271938.2	A2

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 260 AN: 151088 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000597

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000419

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00167

Gnomad OTH AF: 0.000484

GnomAD3 exomes AF: 0.00219 AC: 465 AN: 212192 Hom.: 1 AF XY: 0.00236 AC XY: 268 AN XY: 113550

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000634

Gnomad SAS exome AF: 0.00204

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.00275

GnomAD4 exome AF: 0.00213 AC: 3068 AN: 1437248 Hom.: 8 Cov.: 32 AF XY: 0.00217 AC XY: 1549 AN XY: 712422

Gnomad4 AFR exome AF: 0.000212

Gnomad4 AMR exome AF: 0.000416

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000777

Gnomad4 SAS exome AF: 0.00182

Gnomad4 FIN exome AF: 0.00968

Gnomad4 NFE exome AF: 0.00204

Gnomad4 OTH exome AF: 0.00206

GnomAD4 genome AF: 0.00172 AC: 260 AN: 151206 Hom.: 0 Cov.: 27 AF XY: 0.00199 AC XY: 147 AN XY: 73790

Gnomad4 AFR AF: 0.000267

Gnomad4 AMR AF: 0.000596

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000420

Gnomad4 FIN AF: 0.0118

Gnomad4 NFE AF: 0.00167

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.000903

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MEGF8-related Carpenter syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 21, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

MEGF8: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.054
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs145886667; hg19: chr19-42874888;