12-52360891-A-G

Position:

• chr12-52360891-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002283.4(KRT85):​c.1486T>C​(p.Phe496Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KRT85 NM_002283.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28

Genes affected

KRT85 (HGNC:6462): (keratin 85) The protein encoded by this gene is a member of the keratin gene family. As a type II hair keratin, it is a basic protein which heterodimerizes with type I keratins to form hair and nails. The type II hair keratins are clustered in a region of chromosome 12q13 and are grouped into two distinct subfamilies based on structure similarity. One subfamily, consisting of KRTHB1, KRTHB3, and KRTHB6, is highly related. The other less-related subfamily includes KRTHB2, KRTHB4, and KRTHB5. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16498867).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT85	NM_002283.4	c.1486T>C	p.Phe496Leu	missense_variant	9/9	ENST00000257901.7	NP_002274.1
KRT85	NM_001300810.1	c.850T>C	p.Phe284Leu	missense_variant	7/7		NP_001287739.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT85	ENST00000257901.7	c.1486T>C	p.Phe496Leu	missense_variant	9/9	1	NM_002283.4	ENSP00000257901.3
KRT85	ENST00000544265.1	c.850T>C	p.Phe284Leu	missense_variant	7/7	2		ENSP00000440240.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460112 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726360

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2023

The c.1486T>C (p.F496L) alteration is located in exon 9 (coding exon 9) of the KRT85 gene. This alteration results from a T to C substitution at nucleotide position 1486, causing the phenylalanine (F) at amino acid position 496 to be replaced by a leucine (L). 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	Uncertain	0.49
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.57
DEOGEN2	Benign	0.054	T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.15	T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.090	N;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.40	N;N
REVEL	Benign	0.19
Sift	Benign	0.66	T;T
Sift4G	Benign	0.68	T;T
Polyphen		0.064	B;.
Vest4		0.43
MutPred		0.28		Gain of catalytic residue at S500 (P = 0.0059);.;
MVP		0.81
MPC		0.39
ClinPred		0.15	T
GERP RS		4.1
Varity_R		0.055
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs970931843; hg19: chr12-52754675;