12-52771095-C-A

Variant names:

• chr12-52771095-C-A
• rs199634546
• NM_015848.4:c.1388G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015848.4(KRT76):​c.1388G>T​(p.Arg463Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R463Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRT76 NM_015848.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.983

Genes affected

KRT76 (HGNC:24430): (keratin 76) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins. The type II keratins are clustered in a region of chromosome 12q13. [provided by RefSeq, Jun 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT76	NM_015848.4	c.1388G>T	p.Arg463Leu	missense_variant	Exon 7 of 9	ENST00000332411.2	NP_056932.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT76	ENST00000332411.2	c.1388G>T	p.Arg463Leu	missense_variant	Exon 7 of 9	1	NM_015848.4	ENSP00000330101.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460528 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726556

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111682

Other (OTH) AF: 0.00 AC: 0 AN: 60298

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		0.98
PrimateAI	Benign	0.20	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.026	D
Polyphen		0.99	D
Vest4		0.69
MutPred		0.63		Loss of MoRF binding (P = 0.0076);
MVP		0.82
MPC		0.36
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.43
gMVP		0.50
Mutation Taster		=35/65	disease causing

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

Publications

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Other links and lift over

dbSNP: rs199634546; hg19: chr12-53164879;