12-52567052-T-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.1507A>G(p.Thr503Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,596,900 control chromosomes in the GnomAD database, including 568 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (67 hom., cov: 32)
  • Exomes 𝑓: 0.017 (501 hom.)
• Consequence: KRT74 NM_175053.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.30

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=0.0016447604).
• BP6: Variant 12-52567052-T-C is Benign according to our data. Variant chr12-52567052-T-C is described in ClinVar as [Benign]. Clinvar id is 1247065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-52567052-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0753 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT74	NM_175053.4	c.1507A>G	p.Thr503Ala	missense_variant	9/9	ENST00000305620.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT74	ENST00000305620.3	c.1507A>G	p.Thr503Ala	missense_variant	9/9	1	NM_175053.4	P1
KRT74	ENST00000549343.5	c.1549A>G	p.Thr517Ala	missense_variant	10/10	5
KRT74	ENST00000546384.1	n.494A>G		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 3178 AN: 152056 Hom.: 67 Cov.: 32

Gnomad AFR AF: 0.0402

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00989

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00695

Gnomad SAS AF: 0.0825

Gnomad FIN AF: 0.00659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0203 AC: 4910 AN: 241442 Hom.: 147 AF XY: 0.0229 AC XY: 2991 AN XY: 130564

Gnomad AFR exome AF: 0.0405

Gnomad AMR exome AF: 0.00616

Gnomad ASJ exome AF: 0.00331

Gnomad EAS exome AF: 0.00709

Gnomad SAS exome AF: 0.0814

Gnomad FIN exome AF: 0.00761

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.0166 AC: 23958 AN: 1444726 Hom.: 501 Cov.: 30 AF XY: 0.0184 AC XY: 13184 AN XY: 716062

Gnomad4 AFR exome AF: 0.0414

Gnomad4 AMR exome AF: 0.00709

Gnomad4 ASJ exome AF: 0.00346

Gnomad4 EAS exome AF: 0.00501

Gnomad4 SAS exome AF: 0.0816

Gnomad4 FIN exome AF: 0.00815

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.0172

GnomAD4 genome AF: 0.0209 AC: 3176 AN: 152174 Hom.: 67 Cov.: 32 AF XY: 0.0210 AC XY: 1560 AN XY: 74392

Gnomad4 AFR AF: 0.0401

Gnomad4 AMR AF: 0.00988

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00696

Gnomad4 SAS AF: 0.0819

Gnomad4 FIN AF: 0.00659

Gnomad4 NFE AF: 0.0119

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0147 Hom.: 21

Bravo AF: 0.0203

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0169 AC: 65

ESP6500AA AF: 0.0409 AC: 180

ESP6500EA AF: 0.0116 AC: 100

ExAC AF: 0.0224 AC: 2723

Asia WGS AF: 0.0470 AC: 164 AN: 3478

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 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	18
Dann	Benign	0.81
DEOGEN2	Benign	0.0095	T;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.31	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.21	N;N
REVEL	Benign	0.096
Sift	Uncertain	0.020	D;D
Sift4G	Benign	0.55	T;T
Polyphen		0.0	.;B
Vest4		0.018
MPC		0.064
ClinPred		0.0066	T
GERP RS		1.7
Varity_R		0.067
gMVP		0.13

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: rs80347085; hg19: chr12-52960836;