12-52567150-C-A

Variant names:

• chr12-52567150-C-A
• rs143217986
• NM_175053.4:c.1409G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_175053.4(KRT74):​c.1409G>T​(p.Ser470Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,602,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: KRT74 NM_175053.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.108
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039164722).
• BS2: High AC in GnomAd4 at 29 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.1409G>T	p.Ser470Ile	missense	Exon 9 of 9	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.1409G>T	p.Ser470Ile	missense	Exon 9 of 9	ENSP00000307240.2	Q7RTS7
	KRT74	ENST00000549343.5	TSL:5	c.1451G>T	p.Ser484Ile	missense	Exon 10 of 10	ENSP00000447447.1	F8W1S1
	KRT74	ENST00000546384.1	TSL:4	n.396G>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000150 AC: 36 AN: 239840 AF XY: 0.000185

Gnomad AFR exome AF: 0.0000635

Gnomad AMR exome AF: 0.000208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000254

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000151 AC: 219 AN: 1449774 Hom.: 0 Cov.: 31 AF XY: 0.000153 AC XY: 110 AN XY: 718998

African (AFR) AF: 0.00 AC: 0 AN: 33294

American (AMR) AF: 0.000204 AC: 9 AN: 44020

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25924

East Asian (EAS) AF: 0.00 AC: 0 AN: 39396

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.000179 AC: 198 AN: 1103382

Other (OTH) AF: 0.000167 AC: 10 AN: 59708

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74440

African (AFR) AF: 0.000120 AC: 5 AN: 41550

American (AMR) AF: 0.000392 AC: 6 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000241 Hom.: 0

Bravo AF: 0.000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000190 AC: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	13
DANN	Benign	0.91
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.11
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.18
Sift	Benign	0.032	D
Sift4G	Uncertain	0.027	D
Polyphen		0.089	B
Vest4		0.27
MVP		0.31
MPC		0.089
ClinPred		0.032	T
GERP RS		2.5
Varity_R		0.073
gMVP		0.24
Mutation Taster		=78/22	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: rs143217986; hg19: chr12-52960934;