13-77617648-A-C

Variant names:

• chr13-77617648-A-C
• rs1310335131
• NM_144777.3:c.1501A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144777.3(SCEL):​c.1501A>C​(p.Asn501His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCEL NM_144777.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46

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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18439925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCEL	NM_144777.3	c.1501A>C	p.Asn501His	missense_variant	Exon 25 of 33	ENST00000349847.4	NP_659001.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCEL	ENST00000349847.4	c.1501A>C	p.Asn501His	missense_variant	Exon 25 of 33	1	NM_144777.3	ENSP00000302579.5
SCEL	ENST00000377246.7	c.1441A>C	p.Asn481His	missense_variant	Exon 24 of 32	1		ENSP00000366454.3
SCEL	ENST00000535157.5	c.1375A>C	p.Asn459His	missense_variant	Exon 23 of 31	2		ENSP00000437895.1
SCEL	ENST00000469982.1	n.*7A>C		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1501A>C (p.N501H) alteration is located in exon 25 (coding exon 24) of the SCEL gene. This alteration results from a A to C substitution at nucleotide position 1501, causing the asparagine (N) at amino acid position 501 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	.;.;T
Eigen	Benign	0.15
Eigen_PC	Benign	0.097
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.59	T;T;T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	.;.;M
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.075
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.031	D;T;D
Polyphen		0.73, 0.43	.;P;B
Vest4		0.21
MutPred		0.36		.;.;Gain of catalytic residue at N502 (P = 0.0597);
MVP		0.34
MPC		0.19
ClinPred		0.84	D
GERP RS		4.4
Varity_R		0.13
gMVP		0.48
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1310335131; hg19: chr13-78191783;