rs947345

Variant names:

• chr1-3507824-G-A
• rs947345
• NM_001409.4:c.1760C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001409.4(MEGF6):​c.1760C>T​(p.Pro587Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0505 in 1,612,602 control chromosomes in the GnomAD database, including 2,351 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.060 (368 hom., cov: 33)
  • Exomes 𝑓: 0.049 (1983 hom.)
• Consequence: MEGF6 NM_001409.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.60
• Publications: 14 publications found

Genes affected

MEGF6 (HGNC:3232): (multiple EGF like domains 6) Predicted to enable calcium ion binding activity. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003544271).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0954 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001409.4. 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
	MEGF6	NM_001409.4	MANE Select	c.1760C>T	p.Pro587Leu	missense	Exon 14 of 37	NP_001400.3
	MEGF6	NM_001410718.1		c.1445C>T	p.Pro482Leu	missense	Exon 11 of 34	NP_001397647.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF6	ENST00000356575.9	TSL:1 MANE Select	c.1760C>T	p.Pro587Leu	missense	Exon 14 of 37	ENSP00000348982.4
	MEGF6	ENST00000294599.8	TSL:1	c.1445C>T	p.Pro482Leu	missense	Exon 11 of 30	ENSP00000294599.4
	MEGF6	ENST00000954839.1		c.1637C>T	p.Pro546Leu	missense	Exon 13 of 36	ENSP00000624898.1

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9133 AN: 152114 Hom.: 366 Cov.: 33

Gnomad AFR AF: 0.0975

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0437

Gnomad ASJ AF: 0.0681

Gnomad EAS AF: 0.0496

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.0410

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0483

Gnomad OTH AF: 0.0507

GnomAD2 exomes AF: 0.0473 AC: 11750 AN: 248558 AF XY: 0.0459

Gnomad AFR exome AF: 0.0971

Gnomad AMR exome AF: 0.0331

Gnomad ASJ exome AF: 0.0647

Gnomad EAS exome AF: 0.0508

Gnomad FIN exome AF: 0.0437

Gnomad NFE exome AF: 0.0495

Gnomad OTH exome AF: 0.0513

GnomAD4 exome AF: 0.0495 AC: 72265 AN: 1460368 Hom.: 1983 Cov.: 32 AF XY: 0.0487 AC XY: 35347 AN XY: 726464

African (AFR) AF: 0.0981 AC: 3282 AN: 33466

American (AMR) AF: 0.0362 AC: 1616 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0653 AC: 1706 AN: 26128

East Asian (EAS) AF: 0.0577 AC: 2291 AN: 39690

South Asian (SAS) AF: 0.0228 AC: 1970 AN: 86236

European-Finnish (FIN) AF: 0.0436 AC: 2275 AN: 52226

Middle Eastern (MID) AF: 0.0404 AC: 233 AN: 5766

European-Non Finnish (NFE) AF: 0.0503 AC: 55878 AN: 1111804

Other (OTH) AF: 0.0499 AC: 3014 AN: 60354

GnomAD4 genome AF: 0.0601 AC: 9156 AN: 152234 Hom.: 368 Cov.: 33 AF XY: 0.0588 AC XY: 4375 AN XY: 74436

African (AFR) AF: 0.0979 AC: 4064 AN: 41528

American (AMR) AF: 0.0436 AC: 667 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0681 AC: 236 AN: 3468

East Asian (EAS) AF: 0.0499 AC: 258 AN: 5172

South Asian (SAS) AF: 0.0191 AC: 92 AN: 4826

European-Finnish (FIN) AF: 0.0410 AC: 435 AN: 10606

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0482 AC: 3281 AN: 68022

Other (OTH) AF: 0.0502 AC: 106 AN: 2112

Alfa AF: 0.0531 Hom.: 797

Bravo AF: 0.0644

TwinsUK AF: 0.0475 AC: 176

ALSPAC AF: 0.0496 AC: 191

ESP6500AA AF: 0.0925 AC: 375

ESP6500EA AF: 0.0505 AC: 421

ExAC AF: 0.0471 AC: 5700

Asia WGS AF: 0.0350 AC: 122 AN: 3478

EpiCase AF: 0.0538

EpiControl AF: 0.0556

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-9.6	D
REVEL	Benign	0.21
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.21
MPC		0.53
ClinPred		0.052	T
GERP RS		4.2
Varity_R		0.35
gMVP		0.39
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs947345; hg19: chr1-3424388; COSMIC: COSV53888452;