rs11170177

chr12-52572644-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_175053.4(KRT74):c.495C>G(p.Asn165Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0619 in 1,613,830 control chromosomes in the GnomAD database, including 4,760 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.050 (411 hom., cov: 32)
  • Exomes 𝑓: 0.063 (4349 hom.)
• Consequence: KRT74 NM_175053.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.08

Genes affected

KRT74 (HGNC:28929): (keratin 74) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins. This protein belongs to a family of keratins that are specifically expressed in the inner root sheath of hair follicles.[provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017719865).
• BP6: Variant 12-52572644-G-C is Benign according to our data. Variant chr12-52572644-G-C is described in ClinVar as [Benign]. Clinvar id is 1289755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT74	NM_175053.4	c.495C>G	p.Asn165Lys	missense_variant	2/9	ENST00000305620.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT74	ENST00000305620.3	c.495C>G	p.Asn165Lys	missense_variant	2/9	1	NM_175053.4	P1
KRT74	ENST00000549343.5	c.495C>G	p.Asn165Lys	missense_variant	2/10	5

Frequencies

GnomAD3 genomes AF: 0.0501 AC: 7625 AN: 152124 Hom.: 411 Cov.: 32

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.0615

Gnomad AMR AF: 0.0307

Gnomad ASJ AF: 0.0844

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.0806

Gnomad FIN AF: 0.0398

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0562

Gnomad OTH AF: 0.0526

GnomAD3 exomes AF: 0.0698 AC: 17561 AN: 251432 Hom.: 1218 AF XY: 0.0716 AC XY: 9727 AN XY: 135902

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.0355

Gnomad ASJ exome AF: 0.0820

Gnomad EAS exome AF: 0.303

Gnomad SAS exome AF: 0.0773

Gnomad FIN exome AF: 0.0408

Gnomad NFE exome AF: 0.0543

Gnomad OTH exome AF: 0.0585

GnomAD4 exome AF: 0.0631 AC: 92269 AN: 1461588 Hom.: 4349 Cov.: 34 AF XY: 0.0638 AC XY: 46392 AN XY: 727116

Gnomad4 AFR exome AF: 0.00825

Gnomad4 AMR exome AF: 0.0344

Gnomad4 ASJ exome AF: 0.0835

Gnomad4 EAS exome AF: 0.300

Gnomad4 SAS exome AF: 0.0774

Gnomad4 FIN exome AF: 0.0409

Gnomad4 NFE exome AF: 0.0568

Gnomad4 OTH exome AF: 0.0686

GnomAD4 genome AF: 0.0500 AC: 7619 AN: 152242 Hom.: 411 Cov.: 32 AF XY: 0.0508 AC XY: 3785 AN XY: 74438

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.0306

Gnomad4 ASJ AF: 0.0844

Gnomad4 EAS AF: 0.306

Gnomad4 SAS AF: 0.0800

Gnomad4 FIN AF: 0.0398

Gnomad4 NFE AF: 0.0562

Gnomad4 OTH AF: 0.0554

Alfa AF: 0.0636 Hom.: 367

Bravo AF: 0.0476

TwinsUK AF: 0.0607 AC: 225

ALSPAC AF: 0.0589 AC: 227

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.0549 AC: 472

ExAC AF: 0.0693 AC: 8409

Asia WGS AF: 0.144 AC: 500 AN: 3478

EpiCase AF: 0.0540

EpiControl AF: 0.0557

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.9	T
MutationTaster	Benign	0.00017	P;P
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.35
MutPred		0.43		Gain of ubiquitination at N165 (P = 0.0258);Gain of ubiquitination at N165 (P = 0.0258);
MPC		0.42
ClinPred		0.067	T
GERP RS		3.8
Varity_R		0.91
gMVP		0.76

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: rs11170177; hg19: chr12-52966428;