13-77556598-A-T

Variant names:

• chr13-77556598-A-T
• rs764638067
• NM_144777.3:c.46A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_144777.3(SCEL):​c.46A>T​(p.Met16Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,612,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: SCEL NM_144777.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.391
• Publications: 0 publications found

Genes affected

SCEL (HGNC:10573): (sciellin) The protein encoded by this gene is a precursor to the cornified envelope of terminally differentiated keratinocytes. This protein localizes to the periphery of cells and may function in the assembly or regulation of proteins in the cornified envelope. Transcript variants encoding different isoforms exist. A transcript variant utilizing an alternative polyA signal has been described in the literature, but its full-length nature has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018200189).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144777.3. 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
	SCEL	NM_144777.3	MANE Select	c.46A>T	p.Met16Leu	missense splice_region	Exon 3 of 33	NP_659001.2	O95171-1
	SCEL	NM_003843.4		c.46A>T	p.Met16Leu	missense splice_region	Exon 3 of 32	NP_003834.3
	SCEL	NM_001160706.2		c.46A>T	p.Met16Leu	missense splice_region	Exon 3 of 31	NP_001154178.1	O95171-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCEL	ENST00000349847.4	TSL:1 MANE Select	c.46A>T	p.Met16Leu	missense splice_region	Exon 3 of 33	ENSP00000302579.5	O95171-1
	SCEL	ENST00000377246.7	TSL:1	c.46A>T	p.Met16Leu	missense splice_region	Exon 3 of 32	ENSP00000366454.3	O95171-2
	SCEL	ENST00000856158.1		c.46A>T	p.Met16Leu	missense splice_region	Exon 3 of 33	ENSP00000526217.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000139 AC: 35 AN: 251244 AF XY: 0.0000957

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1460542 Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15 AN XY: 726690

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.000872 AC: 39 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110840

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.000140 AC: 17

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.0
DANN	Benign	0.55
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.39
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.020
Sift	Benign	0.27	T
Sift4G	Benign	0.40	T
Polyphen		0.0010	B
Vest4		0.22
MutPred		0.20		Gain of methylation at K17 (P = 0.0465)
MVP		0.076
MPC		0.049
ClinPred		0.020	T
GERP RS		1.1
Varity_R		0.11
gMVP		0.020
Mutation Taster		=90/10	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: rs764638067; hg19: chr13-78130733;