19-42333494-A-G

Variant names:

• chr19-42333494-A-G
• rs78249686
• NM_001271938.2:c.188-111A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001271938.2(MEGF8):​c.188-111A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 1,225,088 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (31 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (28 hom.)
• Consequence: MEGF8 NM_001271938.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0680
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-42333494-A-G is Benign according to our data. Variant chr19-42333494-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1204223.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0119 (1813/152206) while in subpopulation AFR AF = 0.0413 (1715/41530). AF 95% confidence interval is 0.0397. There are 31 homozygotes in GnomAd4. There are 827 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF8	NM_001271938.2	c.188-111A>G		intron_variant	Intron 1 of 41	ENST00000251268.11	NP_001258867.1
MEGF8	NM_001410.3	c.188-111A>G		intron_variant	Intron 1 of 40		NP_001401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF8	ENST00000251268.11	c.188-111A>G		intron_variant	Intron 1 of 41	5	NM_001271938.2	ENSP00000251268.5
MEGF8	ENST00000334370.8	c.188-111A>G		intron_variant	Intron 1 of 40	1		ENSP00000334219.4
MEGF8	ENST00000378073.5	c.-6898-111A>G		intron_variant	Intron 1 of 40	5		ENSP00000367313.4

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1807 AN: 152088 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.0413

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00813

GnomAD4 exome AF: 0.00122 AC: 1314 AN: 1072882 Hom.: 28 AF XY: 0.00106 AC XY: 567 AN XY: 534424

African (AFR) AF: 0.0414 AC: 1029 AN: 24830

American (AMR) AF: 0.00247 AC: 70 AN: 28362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18342

East Asian (EAS) AF: 0.00 AC: 0 AN: 36458

South Asian (SAS) AF: 0.000143 AC: 9 AN: 63088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37702

Middle Eastern (MID) AF: 0.00180 AC: 6 AN: 3340

European-Non Finnish (NFE) AF: 0.0000811 AC: 66 AN: 813968

Other (OTH) AF: 0.00286 AC: 134 AN: 46792

GnomAD4 genome AF: 0.0119 AC: 1813 AN: 152206 Hom.: 31 Cov.: 33 AF XY: 0.0111 AC XY: 827 AN XY: 74412

African (AFR) AF: 0.0413 AC: 1715 AN: 41530

American (AMR) AF: 0.00431 AC: 66 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67988

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00978 Hom.: 3

Bravo AF: 0.0130

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 27, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.4
DANN	Benign	0.73
PhyloP100		-0.068
Mutation Taster		=100/0	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: rs78249686; hg19: chr19-42837646;