chr19-42333494-A-G

Position:

• chr19-42333494-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF8	NM_001271938.2	c.188-111A>G		intron_variant		ENST00000251268.11	NP_001258867.1
MEGF8	NM_001410.3	c.188-111A>G		intron_variant			NP_001401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF8	ENST00000251268.11	c.188-111A>G		intron_variant		5	NM_001271938.2	ENSP00000251268	A2
MEGF8	ENST00000334370.8	c.188-111A>G		intron_variant		1		ENSP00000334219	P2
MEGF8	ENST00000378073.5	c.-6898-111A>G		intron_variant		5		ENSP00000367313

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

Gnomad4 AFR exome AF: 0.0414

Gnomad4 AMR exome AF: 0.00247

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000143

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000811

Gnomad4 OTH exome AF: 0.00286

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

Gnomad4 AFR AF: 0.0413

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00804

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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.4
DANN	Benign	0.73

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: rs78249686; hg19: chr19-42837646;