NM_175053.4:c.1390+138T>A

Variant names:

• chr12-52567521-A-T
• rs76678410
• NM_175053.4:c.1390+138T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.586
• Publications: 0 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=-0.92).
• BP6: Variant 12-52567521-A-T is Benign according to our data. Variant chr12-52567521-A-T is described in ClinVar as Benign. ClinVar VariationId is 1273296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4906 AD gene.

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.1390+138T>A		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.1390+138T>A		intron	N/A	ENSP00000307240.2	Q7RTS7
	KRT74	ENST00000549343.5	TSL:5	c.1432+138T>A		intron	N/A	ENSP00000447447.1	F8W1S1
	KRT74	ENST00000546384.1	TSL:4	n.377+138T>A		intron	N/A

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

African (AFR) AF: 0.00683 AC: 114 AN: 16694

American (AMR) AF: 0.0135 AC: 496 AN: 36690

Ashkenazi Jewish (ASJ) AF: 0.0419 AC: 833 AN: 19860

East Asian (EAS) AF: 0.000145 AC: 5 AN: 34452

South Asian (SAS) AF: 0.0207 AC: 1326 AN: 64010

European-Finnish (FIN) AF: 0.0709 AC: 3351 AN: 47286

Middle Eastern (MID) AF: 0.0212 AC: 70 AN: 3300

European-Non Finnish (NFE) AF: 0.0478 AC: 16504 AN: 345556

Other (OTH) AF: 0.0348 AC: 1106 AN: 31792

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

African (AFR) AF: 0.00667 AC: 277 AN: 41552

American (AMR) AF: 0.0146 AC: 223 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0433 AC: 150 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4816

European-Finnish (FIN) AF: 0.0738 AC: 782 AN: 10602

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0473 AC: 3214 AN: 68012

Other (OTH) AF: 0.0270 AC: 57 AN: 2112

Alfa AF: 0.0431 Hom.: 21

Bravo AF: 0.0263

Asia WGS AF: 0.00693 AC: 24 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	-0.92
CADD	Benign	0.16
DANN	Benign	0.32
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism

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: rs76678410; hg19: chr12-52961305;