chr19-42333504-A-G

Variant names:

• chr19-42333504-A-G
• rs10421409
• NM_001271938.2:c.188-101A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001271938.2(MEGF8):​c.188-101A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00364 in 1,315,306 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (59 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (60 hom.)
• Consequence: MEGF8 NM_001271938.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.21
• 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 19-42333504-A-G is Benign according to our data. Variant chr19-42333504-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1188295.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF8	NM_001271938.2	c.188-101A>G		intron_variant	Intron 1 of 41	ENST00000251268.11	NP_001258867.1
MEGF8	NM_001410.3	c.188-101A>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.188-101A>G		intron_variant	Intron 1 of 41	5	NM_001271938.2	ENSP00000251268.5
MEGF8	ENST00000334370.8	c.188-101A>G		intron_variant	Intron 1 of 40	1		ENSP00000334219.4
MEGF8	ENST00000378073.5	c.-6898-101A>G		intron_variant	Intron 1 of 40	5		ENSP00000367313.4

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2319 AN: 152170 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.0514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0134

GnomAD4 exome AF: 0.00212 AC: 2465 AN: 1163018 Hom.: 60 AF XY: 0.00197 AC XY: 1139 AN XY: 577722

African (AFR) AF: 0.0591 AC: 1593 AN: 26962

American (AMR) AF: 0.00389 AC: 127 AN: 32654

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 24 AN: 19494

East Asian (EAS) AF: 0.00 AC: 0 AN: 37458

South Asian (SAS) AF: 0.000194 AC: 13 AN: 66972

European-Finnish (FIN) AF: 0.0000248 AC: 1 AN: 40402

Middle Eastern (MID) AF: 0.0148 AC: 54 AN: 3660

European-Non Finnish (NFE) AF: 0.000475 AC: 421 AN: 885538

Other (OTH) AF: 0.00465 AC: 232 AN: 49878

GnomAD4 genome AF: 0.0153 AC: 2323 AN: 152288 Hom.: 59 Cov.: 33 AF XY: 0.0148 AC XY: 1103 AN XY: 74460

African (AFR) AF: 0.0514 AC: 2136 AN: 41564

American (AMR) AF: 0.00693 AC: 106 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68012

Other (OTH) AF: 0.0132 AC: 28 AN: 2116

Alfa AF: 0.00562 Hom.: 9

Bravo AF: 0.0176

Asia WGS AF: 0.00664 AC: 24 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 29, 2019

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	0.23
DANN	Benign	0.69
PhyloP100		-1.2
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: rs10421409; hg19: chr19-42837656;