rs3782489

Positions:

• chr12-52692861-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_175078.3(KRT77):​c.1100C>T​(p.Thr367Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,603,032 control chromosomes in the GnomAD database, including 137,812 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (13099 hom., cov: 29)
  • Exomes 𝑓: 0.37 (124713 hom.)
• Consequence: KRT77 NM_175078.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.19

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005103886).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT77	NM_175078.3	c.1100C>T	p.Thr367Met	missense_variant	6/9	ENST00000341809.8	NP_778253.2
KRT77	XM_011538288.3	c.401C>T	p.Thr134Met	missense_variant	6/9		XP_011536590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT77	ENST00000341809.8	c.1100C>T	p.Thr367Met	missense_variant	6/9	1	NM_175078.3	ENSP00000342710	P1
KRT77	ENST00000553168.1	c.*438C>T		3_prime_UTR_variant, NMD_transcript_variant	7/10	1		ENSP00000448207
	ENST00000547533.1	n.193+64G>A		intron_variant, non_coding_transcript_variant		3
KRT77	ENST00000550823.1	n.747C>T		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes AF: 0.387 AC: 57954 AN: 149668 Hom.: 13068 Cov.: 29

Gnomad AFR AF: 0.425

Gnomad AMI AF: 0.592

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.352

GnomAD3 exomes AF: 0.367 AC: 91635 AN: 249572 Hom.: 20049 AF XY: 0.368 AC XY: 49658 AN XY: 134808

Gnomad AFR exome AF: 0.423

Gnomad AMR exome AF: 0.331

Gnomad ASJ exome AF: 0.394

Gnomad EAS exome AF: 0.240

Gnomad SAS exome AF: 0.401

Gnomad FIN exome AF: 0.413

Gnomad NFE exome AF: 0.372

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.373 AC: 542447 AN: 1453250 Hom.: 124713 Cov.: 41 AF XY: 0.374 AC XY: 270144 AN XY: 723008

Gnomad4 AFR exome AF: 0.426

Gnomad4 AMR exome AF: 0.336

Gnomad4 ASJ exome AF: 0.396

Gnomad4 EAS exome AF: 0.218

Gnomad4 SAS exome AF: 0.403

Gnomad4 FIN exome AF: 0.413

Gnomad4 NFE exome AF: 0.375

Gnomad4 OTH exome AF: 0.369

GnomAD4 genome AF: 0.387 AC: 58020 AN: 149782 Hom.: 13099 Cov.: 29 AF XY: 0.387 AC XY: 28349 AN XY: 73198

Gnomad4 AFR AF: 0.425

Gnomad4 AMR AF: 0.356

Gnomad4 ASJ AF: 0.389

Gnomad4 EAS AF: 0.239

Gnomad4 SAS AF: 0.431

Gnomad4 FIN AF: 0.418

Gnomad4 NFE AF: 0.373

Gnomad4 OTH AF: 0.357

Alfa AF: 0.376 Hom.: 16424

ESP6500AA AF: 0.420 AC: 1850

ESP6500EA AF: 0.369 AC: 3151

ExAC AF: 0.369 AC: 44643

Asia WGS AF: 0.396 AC: 1372 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.030
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.27
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.029	D
Polyphen		1.0	D
Vest4		0.055
MPC		0.36
ClinPred		0.060	T
GERP RS		1.4
Varity_R		0.11
gMVP		0.34

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: rs3782489; hg19: chr12-53086645; COSMIC: COSV59239091;