12-52692610-G-A

Variant summary

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

The NM_175078.3(KRT77):c.1238C>T(p.Ala413Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000712 in 1,403,618 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: KRT77 NM_175078.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.78

Genes affected

KRT77 (HGNC:20411): (keratin 77) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins. This gene encodes an epithelial keratin that is expressed in the skin and eccrine sweat glands. The type II keratins are clustered in a region of chromosome 12q13.[provided by RefSeq, Jun 2009]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT77	NM_175078.3	c.1238C>T	p.Ala413Val	missense_variant	7/9	ENST00000341809.8
KRT77	XM_011538288.3	c.539C>T	p.Ala180Val	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT77	ENST00000341809.8	c.1238C>T	p.Ala413Val	missense_variant	7/9	1	NM_175078.3	P1
	ENST00000547533.1	n.6G>A		non_coding_transcript_exon_variant	1/3	3
KRT77	ENST00000553168.1	c.*576C>T		3_prime_UTR_variant, NMD_transcript_variant	8/10	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1403618 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 696748

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: 9.38e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Mar 17, 2023

The c.1238C>T (p.A413V) alteration is located in exon 7 (coding exon 7) of the KRT77 gene. This alteration results from a C to T substitution at nucleotide position 1238, causing the alanine (A) at amino acid position 413 to be replaced by a valine (V). 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	0.22
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.30
MutPred		0.40		Loss of phosphorylation at S411 (P = 0.2033);
MVP		0.97
MPC		0.73
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.71
gMVP		0.18

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: rs1182747693; hg19: chr12-53086394;