19-42326085-A-T

Variant names:

• chr19-42326085-A-T
• rs111536758
• NM_001271938.2:c.-159A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001271938.2(MEGF8):​c.-159A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00419 in 1,224,890 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (91 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (71 hom.)
• Consequence: MEGF8 NM_001271938.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.108
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-42326085-A-T is Benign according to our data. Variant chr19-42326085-A-T is described in ClinVar as [Benign]. Clinvar id is 1283337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF8	NM_001271938.2	c.-159A>T		5_prime_UTR_variant	Exon 1 of 42	ENST00000251268.11	NP_001258867.1
MEGF8	NM_001410.3	c.-159A>T		5_prime_UTR_variant	Exon 1 of 41		NP_001401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF8	ENST00000251268.11	c.-159A>T		5_prime_UTR_variant	Exon 1 of 42	5	NM_001271938.2	ENSP00000251268.5
MEGF8	ENST00000334370.8	c.-159A>T		5_prime_UTR_variant	Exon 1 of 41	1		ENSP00000334219.4
MEGF8	ENST00000378073.5	c.-7244A>T		5_prime_UTR_variant	Exon 1 of 41	5		ENSP00000367313.4

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2746 AN: 152088 Hom.: 83 Cov.: 32

Gnomad AFR AF: 0.0612

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00831

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: 0.000618

Gnomad OTH AF: 0.0148

GnomAD4 exome AF: 0.00220 AC: 2355 AN: 1072684 Hom.: 71 Cov.: 15 AF XY: 0.00210 AC XY: 1090 AN XY: 519632

African (AFR) AF: 0.0733 AC: 1539 AN: 20998

American (AMR) AF: 0.00511 AC: 46 AN: 9010

Ashkenazi Jewish (ASJ) AF: 0.00135 AC: 22 AN: 16292

East Asian (EAS) AF: 0.00 AC: 0 AN: 26400

South Asian (SAS) AF: 0.000299 AC: 13 AN: 43486

European-Finnish (FIN) AF: 0.0000269 AC: 1 AN: 37216

Middle Eastern (MID) AF: 0.0166 AC: 52 AN: 3138

European-Non Finnish (NFE) AF: 0.000452 AC: 394 AN: 870848

Other (OTH) AF: 0.00636 AC: 288 AN: 45296

GnomAD4 genome AF: 0.0183 AC: 2782 AN: 152206 Hom.: 91 Cov.: 32 AF XY: 0.0180 AC XY: 1340 AN XY: 74408

African (AFR) AF: 0.0619 AC: 2570 AN: 41510

American (AMR) AF: 0.00830 AC: 127 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000618 AC: 42 AN: 68000

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.0121 Hom.: 9

Bravo AF: 0.0209

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 29, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.5
DANN	Benign	0.80
PhyloP100		0.11
PromoterAI		0.018	Neutral
Mutation Taster		=299/1	polymorphism (auto)

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: rs111536758; hg19: chr19-42830237;