rs35473255

Variant names:

• chr19-42354596-C-T
• rs35473255
• NM_001271938.2:c.4020C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001271938.2(MEGF8):​c.4020C>T​(p.Tyr1340Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.006 in 1,612,110 control chromosomes in the GnomAD database, including 434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (219 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (215 hom.)
• Consequence: MEGF8 NM_001271938.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.25
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 19-42354596-C-T is Benign according to our data. Variant chr19-42354596-C-T is described in ClinVar as Benign. ClinVar VariationId is 473330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

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.4020C>T	p.Tyr1340Tyr	synonymous	Exon 23 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.3819C>T	p.Tyr1273Tyr	synonymous	Exon 22 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.4020C>T	p.Tyr1340Tyr	synonymous	Exon 23 of 42	ENSP00000251268.5	Q7Z7M0-1
	MEGF8	ENST00000334370.8	TSL:1	c.3819C>T	p.Tyr1273Tyr	synonymous	Exon 22 of 41	ENSP00000334219.4	Q7Z7M0-2
	MEGF8	ENST00000378073.5	TSL:5	c.-3066C>T		5_prime_UTR_premature_start_codon_gain	Exon 23 of 41	ENSP00000367313.4	F5GZG7

Frequencies

GnomAD3 genomes AF: 0.0305 AC: 4639 AN: 152176 Hom.: 218 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00442

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.00897 AC: 2243 AN: 250084 AF XY: 0.00686

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.00664

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00424

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000672

Gnomad OTH exome AF: 0.00640

GnomAD4 exome AF: 0.00344 AC: 5025 AN: 1459816 Hom.: 215 Cov.: 31 AF XY: 0.00294 AC XY: 2132 AN XY: 726032

African (AFR) AF: 0.107 AC: 3575 AN: 33460

American (AMR) AF: 0.00746 AC: 333 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.000651 AC: 17 AN: 26106

East Asian (EAS) AF: 0.00194 AC: 77 AN: 39660

South Asian (SAS) AF: 0.000418 AC: 36 AN: 86152

European-Finnish (FIN) AF: 0.0000949 AC: 5 AN: 52682

Middle Eastern (MID) AF: 0.00885 AC: 51 AN: 5762

European-Non Finnish (NFE) AF: 0.000375 AC: 417 AN: 1111024

Other (OTH) AF: 0.00852 AC: 514 AN: 60316

GnomAD4 genome AF: 0.0305 AC: 4642 AN: 152294 Hom.: 219 Cov.: 32 AF XY: 0.0295 AC XY: 2194 AN XY: 74460

African (AFR) AF: 0.105 AC: 4351 AN: 41528

American (AMR) AF: 0.0114 AC: 175 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00443 AC: 23 AN: 5190

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68032

Other (OTH) AF: 0.0189 AC: 40 AN: 2116

Alfa AF: 0.0168 Hom.: 87

Bravo AF: 0.0346

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: 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	-0.52
CADD	Benign	2.6
DANN	Benign	0.58
PhyloP100		-1.3
Mutation Taster		=100/0	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: rs35473255; hg19: chr19-42858748; COSMIC: COSV104379234;