19-42357415-C-T

Variant names:

• chr19-42357415-C-T
• rs35468447
• NM_001271938.2:c.4842C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001271938.2(MEGF8):​c.4842C>T​(p.Thr1614Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,613,256 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (40 hom.)
• Consequence: MEGF8 NM_001271938.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.356
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 19-42357415-C-T is Benign according to our data. Variant chr19-42357415-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 540557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.356 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0113 (1725/152240) while in subpopulation AFR AF = 0.0339 (1406/41530). AF 95% confidence interval is 0.0324. There are 21 homozygotes in GnomAd4. There are 807 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 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.4842C>T	p.Thr1614Thr	synonymous	Exon 28 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.4641C>T	p.Thr1547Thr	synonymous	Exon 27 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.4842C>T	p.Thr1614Thr	synonymous	Exon 28 of 42	ENSP00000251268.5	Q7Z7M0-1
	MEGF8	ENST00000334370.8	TSL:1	c.4641C>T	p.Thr1547Thr	synonymous	Exon 27 of 41	ENSP00000334219.4	Q7Z7M0-2
	MEGF8	ENST00000378073.5	TSL:5	c.-2244C>T		5_prime_UTR_premature_start_codon_gain	Exon 28 of 41	ENSP00000367313.4	F5GZG7

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1724 AN: 152122 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00975

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00428 AC: 1070 AN: 249730 AF XY: 0.00366

Gnomad AFR exome AF: 0.0362

Gnomad AMR exome AF: 0.00570

Gnomad ASJ exome AF: 0.00670

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00151

Gnomad OTH exome AF: 0.00541

GnomAD4 exome AF: 0.00228 AC: 3332 AN: 1461016 Hom.: 40 Cov.: 32 AF XY: 0.00215 AC XY: 1565 AN XY: 726798

African (AFR) AF: 0.0360 AC: 1206 AN: 33476

American (AMR) AF: 0.00611 AC: 273 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00786 AC: 205 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86214

European-Finnish (FIN) AF: 0.000113 AC: 6 AN: 53200

Middle Eastern (MID) AF: 0.0145 AC: 83 AN: 5738

European-Non Finnish (NFE) AF: 0.00106 AC: 1181 AN: 1111554

Other (OTH) AF: 0.00590 AC: 356 AN: 60348

GnomAD4 genome AF: 0.0113 AC: 1725 AN: 152240 Hom.: 21 Cov.: 32 AF XY: 0.0108 AC XY: 807 AN XY: 74426

African (AFR) AF: 0.0339 AC: 1406 AN: 41530

American (AMR) AF: 0.00974 AC: 149 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00779 AC: 27 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00144 AC: 98 AN: 68000

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.00619 Hom.: 7

Bravo AF: 0.0134

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00249

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	MEGF8-related Carpenter syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.28
DANN	Benign	0.72
PhyloP100		-0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	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: rs35468447; hg19: chr19-42861567; COSMIC: COSV52078772; COSMIC: COSV52078772;