12-52567521-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_175053.4(KRT74):c.1390+138T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0382 in 751,882 control chromosomes in the GnomAD database, including 734 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.032 (113 hom., cov: 32)
  • Exomes 𝑓: 0.040 (621 hom.)
• Consequence: KRT74 NM_175053.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.586

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-52567521-A-T is Benign according to our data. Variant chr12-52567521-A-T is described in ClinVar as [Benign]. Clinvar id is 1273296.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0322 (4906/152242) while in subpopulation NFE AF= 0.0473 (3214/68012). AF 95% confidence interval is 0.0459. There are 113 homozygotes in gnomad4. There are 2388 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 4908 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT74	NM_175053.4	c.1390+138T>A		intron_variant		ENST00000305620.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT74	ENST00000305620.3	c.1390+138T>A		intron_variant		1	NM_175053.4	P1
KRT74	ENST00000549343.5	c.1432+138T>A		intron_variant		5
KRT74	ENST00000546384.1	n.377+138T>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0323 AC: 4908 AN: 152124 Hom.: 113 Cov.: 32

Gnomad AFR AF: 0.00669

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.0433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.0738

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0473

Gnomad OTH AF: 0.0273

GnomAD4 exome AF: 0.0397 AC: 23805 AN: 599640 Hom.: 621 AF XY: 0.0393 AC XY: 12670 AN XY: 322508

Gnomad4 AFR exome AF: 0.00683

Gnomad4 AMR exome AF: 0.0135

Gnomad4 ASJ exome AF: 0.0419

Gnomad4 EAS exome AF: 0.000145

Gnomad4 SAS exome AF: 0.0207

Gnomad4 FIN exome AF: 0.0709

Gnomad4 NFE exome AF: 0.0478

Gnomad4 OTH exome AF: 0.0348

GnomAD4 genome AF: 0.0322 AC: 4906 AN: 152242 Hom.: 113 Cov.: 32 AF XY: 0.0321 AC XY: 2388 AN XY: 74428

Gnomad4 AFR AF: 0.00667

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.0433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0199

Gnomad4 FIN AF: 0.0738

Gnomad4 NFE AF: 0.0473

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0431 Hom.: 21

Bravo AF: 0.0263

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 21, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.16
Dann	Benign	0.32

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: rs76678410; hg19: chr12-52961305;