chr12-52567369-C-A

Variant names:

• chr12-52567369-C-A
• rs653956
• NM_175053.4:c.1391-201G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_175053.4(KRT74):​c.1391-201G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.746 in 151,502 control chromosomes in the GnomAD database, including 43,462 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.75 (43462 hom., cov: 31)
• Consequence: KRT74 NM_175053.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.17
• Publications: 2 publications found

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]

KRT74 Gene-Disease associations (from GenCC):

• autosomal dominant wooly hair

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hypotrichosis 3

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• hypotrichosis simplex of the scalp

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated familial wooly hair disorder

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pure hair and nail ectodermal dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-52567369-C-A is Benign according to our data. Variant chr12-52567369-C-A is described in ClinVar as Benign. ClinVar VariationId is 1243772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.933 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175053.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT74	NM_175053.4	MANE Select	c.1391-201G>T		intron	N/A	NP_778223.2	Q7RTS7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT74	ENST00000305620.3	TSL:1 MANE Select	c.1391-201G>T		intron	N/A	ENSP00000307240.2	Q7RTS7
	KRT74	ENST00000549343.5	TSL:5	c.1433-201G>T		intron	N/A	ENSP00000447447.1	F8W1S1
	KRT74	ENST00000546384.1	TSL:4	n.378-201G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.746 AC: 112957 AN: 151386 Hom.: 43398 Cov.: 31

Gnomad AFR AF: 0.941

Gnomad AMI AF: 0.741

Gnomad AMR AF: 0.623

Gnomad ASJ AF: 0.588

Gnomad EAS AF: 0.659

Gnomad SAS AF: 0.751

Gnomad FIN AF: 0.695

Gnomad MID AF: 0.651

Gnomad NFE AF: 0.679

Gnomad OTH AF: 0.706

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.746 AC: 113076 AN: 151502 Hom.: 43462 Cov.: 31 AF XY: 0.742 AC XY: 54909 AN XY: 73998

African (AFR) AF: 0.941 AC: 38934 AN: 41372

American (AMR) AF: 0.623 AC: 9502 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 2033 AN: 3460

East Asian (EAS) AF: 0.659 AC: 3383 AN: 5134

South Asian (SAS) AF: 0.751 AC: 3601 AN: 4796

European-Finnish (FIN) AF: 0.695 AC: 7276 AN: 10470

Middle Eastern (MID) AF: 0.653 AC: 188 AN: 288

European-Non Finnish (NFE) AF: 0.679 AC: 46002 AN: 67730

Other (OTH) AF: 0.707 AC: 1484 AN: 2100

Alfa AF: 0.806 Hom.: 11575

Bravo AF: 0.745

Asia WGS AF: 0.755 AC: 2627 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.089
DANN	Benign	0.42
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs653956; hg19: chr12-52961153;