rs149279834

Variant names:

• chr19-42356864-C-T
• rs149279834
• NM_001271938.2:c.4713C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-42356864-C-T
• chr19-42356864-C-A

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.4713C>T​(p.Ala1571Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00955 in 1,589,726 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (118 hom.)
• Consequence: MEGF8 NM_001271938.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.88
• Publications: 0 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=-0.63).
• BP6: Variant 19-42356864-C-T is Benign according to our data. Variant chr19-42356864-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.88 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00699 (1064/152326) while in subpopulation SAS AF = 0.0337 (163/4834). AF 95% confidence interval is 0.0295. There are 15 homozygotes in GnomAd4. There are 551 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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.4713C>T	p.Ala1571Ala	synonymous	Exon 27 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.4512C>T	p.Ala1504Ala	synonymous	Exon 26 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.4713C>T	p.Ala1571Ala	synonymous	Exon 27 of 42	ENSP00000251268.5	Q7Z7M0-1
	MEGF8	ENST00000334370.8	TSL:1	c.4512C>T	p.Ala1504Ala	synonymous	Exon 26 of 41	ENSP00000334219.4	Q7Z7M0-2
	MEGF8	ENST00000378073.5	TSL:5	c.-2373C>T		5_prime_UTR_premature_start_codon_gain	Exon 27 of 41	ENSP00000367313.4	F5GZG7

Frequencies

GnomAD3 genomes AF: 0.00702 AC: 1069 AN: 152208 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0347

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00851

Gnomad OTH AF: 0.0125

GnomAD2 exomes AF: 0.0102 AC: 2159 AN: 212094 AF XY: 0.0120

Gnomad AFR exome AF: 0.00102

Gnomad AMR exome AF: 0.00639

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.0000635

Gnomad FIN exome AF: 0.00314

Gnomad NFE exome AF: 0.00867

Gnomad OTH exome AF: 0.00938

GnomAD4 exome AF: 0.00982 AC: 14118 AN: 1437400 Hom.: 118 Cov.: 32 AF XY: 0.0107 AC XY: 7653 AN XY: 712720

African (AFR) AF: 0.00115 AC: 38 AN: 33036

American (AMR) AF: 0.00711 AC: 290 AN: 40808

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 463 AN: 25596

East Asian (EAS) AF: 0.0000521 AC: 2 AN: 38382

South Asian (SAS) AF: 0.0335 AC: 2755 AN: 82126

European-Finnish (FIN) AF: 0.00270 AC: 139 AN: 51478

Middle Eastern (MID) AF: 0.0307 AC: 176 AN: 5724

European-Non Finnish (NFE) AF: 0.00873 AC: 9613 AN: 1100786

Other (OTH) AF: 0.0108 AC: 642 AN: 59464

GnomAD4 genome AF: 0.00699 AC: 1064 AN: 152326 Hom.: 15 Cov.: 32 AF XY: 0.00740 AC XY: 551 AN XY: 74488

African (AFR) AF: 0.00173 AC: 72 AN: 41554

American (AMR) AF: 0.00843 AC: 129 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0337 AC: 163 AN: 4834

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10630

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00853 AC: 580 AN: 68028

Other (OTH) AF: 0.0123 AC: 26 AN: 2110

Alfa AF: 0.00650 Hom.: 1

Bravo AF: 0.00635

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.8
DANN	Benign	0.55
PhyloP100		-1.9
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs149279834; hg19: chr19-42861016; COSMIC: COSV104379412;