13-77567720-A-G

Variant names:

• chr13-77567720-A-G
• rs146995012
• NM_144777.3:c.331A>G

Variant summary

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

The NM_144777.3(SCEL):​c.331A>G​(p.Asn111Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000578 in 1,608,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/25 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: SCEL NM_144777.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38

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=0.017668426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCEL	NM_144777.3	c.331A>G	p.Asn111Asp	missense_variant	Exon 6 of 33	ENST00000349847.4	NP_659001.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCEL	ENST00000349847.4	c.331A>G	p.Asn111Asp	missense_variant	Exon 6 of 33	1	NM_144777.3	ENSP00000302579.5
SCEL	ENST00000377246.7	c.331A>G	p.Asn111Asp	missense_variant	Exon 6 of 32	1		ENSP00000366454.3
SCEL	ENST00000535157.5	c.331A>G	p.Asn111Asp	missense_variant	Exon 6 of 31	2		ENSP00000437895.1
SCEL	ENST00000471491.5	n.291-575A>G		intron_variant	Intron 5 of 18	2		ENSP00000432840.1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000808 AC: 20 AN: 247562 AF XY: 0.0000523

Gnomad AFR exome AF: 0.00118

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000350 AC: 51 AN: 1455914 Hom.: 0 Cov.: 28 AF XY: 0.0000318 AC XY: 23 AN XY: 724398

Gnomad4 AFR exome AF: 0.00136 AC: 45 AN: 33164

Gnomad4 AMR exome AF: 0.0000229 AC: 1 AN: 43630

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26012

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39498

Gnomad4 SAS exome AF: 0.0000117 AC: 1 AN: 85270

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53250

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1109168

Gnomad4 Remaining exome AF: 0.0000665 AC: 4 AN: 60168

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74508

Gnomad4 AFR AF: 0.000938 AC: 0.000938041 AN: 0.000938041

Gnomad4 AMR AF: 0.000196 AC: 0.000195976 AN: 0.000195976

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000140 Hom.: 0

Bravo AF: 0.000321

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.331A>G (p.N111D) alteration is located in exon 6 (coding exon 5) of the SCEL gene. This alteration results from a A to G substitution at nucleotide position 331, causing the asparagine (N) at amino acid position 111 to be replaced by an aspartic acid (D). 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	0.13
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.073	.;.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.091
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;L
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.032
Sift	Benign	0.082	T;T;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.37, 0.57	.;B;P
Vest4		0.19
MVP		0.25
MPC		0.17
ClinPred		0.052	T
GERP RS		2.5
Varity_R		0.090
gMVP		0.12
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -40

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

Publications

LitVar

Other links and lift over

dbSNP: rs146995012; hg19: chr13-78141855;