rs139192223

chr19-42375804-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_001271938.2(MEGF8):c.7567A>G(p.Thr2523Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000947 in 1,612,540 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (2 hom.)
• Consequence: MEGF8 NM_001271938.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.529

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058243275).
• BP6: Variant 19-42375804-A-G is Benign according to our data. Variant chr19-42375804-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 565484.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-42375804-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00075 (114/152010) while in subpopulation NFE AF= 0.00134 (91/67962). AF 95% confidence interval is 0.00112. There are 0 homozygotes in gnomad4. There are 55 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2	c.7567A>G	p.Thr2523Ala	missense_variant	42/42	ENST00000251268.11
MEGF8	NM_001410.3	c.7366A>G	p.Thr2456Ala	missense_variant	41/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11	c.7567A>G	p.Thr2523Ala	missense_variant	42/42	5	NM_001271938.2	A2

Frequencies

GnomAD3 genomes AF: 0.000751 AC: 114 AN: 151892 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000734 AC: 181 AN: 246646 Hom.: 1 AF XY: 0.000775 AC XY: 104 AN XY: 134280

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000668

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000932

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000967 AC: 1413 AN: 1460530 Hom.: 2 Cov.: 31 AF XY: 0.000955 AC XY: 694 AN XY: 726526

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000806

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000762

Gnomad4 NFE exome AF: 0.00117

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.000750 AC: 114 AN: 152010 Hom.: 0 Cov.: 32 AF XY: 0.000740 AC XY: 55 AN XY: 74282

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00131 Hom.: 1

Bravo AF: 0.000850

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000684 AC: 83

EpiCase AF: 0.00224

EpiControl AF: 0.00166

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

MEGF8-related Carpenter syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	15
Dann	Benign	0.30
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.0058	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.90	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.022
Sift	Benign	0.69	T;T;T
Sift4G	Benign	0.99	T;D;T
Polyphen		0.0070	B;B;B
Vest4		0.078
MVP		0.082
MPC		0.55
ClinPred		0.0060	T
GERP RS		2.6
Varity_R		0.045
gMVP		0.47

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: rs139192223; hg19: chr19-42879956;