rs115335139

Variant names:

• chr19-42353010-C-T
• rs115335139
• NM_001271938.2:c.3433C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001271938.2(MEGF8):​c.3433C>T​(p.Leu1145Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,572,338 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (34 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (38 hom.)
• Consequence: MEGF8 NM_001271938.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.627
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
• Carpenter syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 19-42353010-C-T is Benign according to our data. Variant chr19-42353010-C-T is described in ClinVar as Benign. ClinVar VariationId is 473326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.627 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0124 (1896/152310) while in subpopulation AFR AF = 0.043 (1787/41552). AF 95% confidence interval is 0.0413. There are 34 homozygotes in GnomAd4. There are 875 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271938.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	NM_001271938.2	MANE Select	c.3433C>T	p.Leu1145Leu	synonymous	Exon 20 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.3232C>T	p.Leu1078Leu	synonymous	Exon 19 of 41	NP_001401.2	Q7Z7M0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	ENST00000251268.11	TSL:5 MANE Select	c.3433C>T	p.Leu1145Leu	synonymous	Exon 20 of 42	ENSP00000251268.5	Q7Z7M0-1
	MEGF8	ENST00000334370.8	TSL:1	c.3232C>T	p.Leu1078Leu	synonymous	Exon 19 of 41	ENSP00000334219.4	Q7Z7M0-2
	MEGF8	ENST00000378073.5	TSL:5	c.-3653C>T		5_prime_UTR_premature_start_codon_gain	Exon 20 of 41	ENSP00000367313.4	F5GZG7

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1889 AN: 152192 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.0430

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00296 AC: 538 AN: 181502 AF XY: 0.00214

Gnomad AFR exome AF: 0.0432

Gnomad AMR exome AF: 0.00279

Gnomad ASJ exome AF: 0.000114

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000144

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.00126 AC: 1790 AN: 1420028 Hom.: 38 Cov.: 33 AF XY: 0.00107 AC XY: 755 AN XY: 702616

African (AFR) AF: 0.0430 AC: 1390 AN: 32328

American (AMR) AF: 0.00258 AC: 100 AN: 38706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25320

East Asian (EAS) AF: 0.0000270 AC: 1 AN: 37066

South Asian (SAS) AF: 0.000136 AC: 11 AN: 80726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50182

Middle Eastern (MID) AF: 0.00177 AC: 10 AN: 5638

European-Non Finnish (NFE) AF: 0.0000935 AC: 102 AN: 1091210

Other (OTH) AF: 0.00299 AC: 176 AN: 58852

GnomAD4 genome AF: 0.0124 AC: 1896 AN: 152310 Hom.: 34 Cov.: 33 AF XY: 0.0117 AC XY: 875 AN XY: 74472

African (AFR) AF: 0.0430 AC: 1787 AN: 41552

American (AMR) AF: 0.00457 AC: 70 AN: 15314

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

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68016

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00821 Hom.: 10

Bravo AF: 0.0137

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	MEGF8-related Carpenter syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.7
DANN	Benign	0.54
PhyloP100		0.63
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs115335139; hg19: chr19-42857162; COSMIC: COSV104379233;