12-52567044-C-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_175053.4(KRT74):c.1515G>T(p.Ala505=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000359 in 1,599,490 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: KRT74 NM_175053.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.184

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 12-52567044-C-A is Benign according to our data. Variant chr12-52567044-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 712119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.184 with no splicing effect.
• BS2: High AC in GnomAd at 316 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT74	NM_175053.4	c.1515G>T	p.Ala505=	synonymous_variant	9/9	ENST00000305620.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT74	ENST00000305620.3	c.1515G>T	p.Ala505=	synonymous_variant	9/9	1	NM_175053.4	P1
KRT74	ENST00000549343.5	c.1557G>T	p.Ala519=	synonymous_variant	10/10	5
KRT74	ENST00000546384.1	n.502G>T		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 316 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00713

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000516 AC: 124 AN: 240174 Hom.: 0 AF XY: 0.000339 AC XY: 44 AN XY: 129776

Gnomad AFR exome AF: 0.00650

Gnomad AMR exome AF: 0.0000902

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000606

Gnomad SAS exome AF: 0.0000696

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000279

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000178 AC: 258 AN: 1447286 Hom.: 1 Cov.: 30 AF XY: 0.000145 AC XY: 104 AN XY: 718004

Gnomad4 AFR exome AF: 0.00636

Gnomad4 AMR exome AF: 0.000137

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000203

Gnomad4 SAS exome AF: 0.0000355

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000453

Gnomad4 OTH exome AF: 0.000419

GnomAD4 genome AF: 0.00208 AC: 316 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74402

Gnomad4 AFR AF: 0.00711

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000780 Hom.: 0

Bravo AF: 0.00233

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KRT74-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	0.62
Dann	Benign	0.51

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: rs114132371; hg19: chr12-52960828;