NM_001386841.1:c.209G>T

Variant names:

• chr17-41184646-C-A
• rs74712790
• NM_001386841.1:c.209G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001386841.1(KRTAP4-1):​c.209G>T​(p.Cys70Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000665 in 150,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 22)
• Consequence: KRTAP4-1 NM_001386841.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.904
• Publications: 0 publications found

Genes affected

KRTAP4-1 (HGNC:18907): (keratin associated protein 4-1) This protein is a member of the keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. KAP family members appear to have unique, family-specific amino- and carboxyl-terminal regions and are subdivided into three multi-gene families according to amino acid composition: the high sulfur, the ultrahigh sulfur, and the high tyrosine/glycine KAPs. This protein is a member of the ultrahigh sulfur KAP family and the gene is localized to a cluster of KAPs at 17q12-q21. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37544933).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386841.1. 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
	KRTAP4-1	NM_001386841.1	MANE Select	c.209G>T	p.Cys70Phe	missense	Exon 1 of 1	NP_001373770.1	Q9BYQ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-1	ENST00000398472.2	TSL:6 MANE Select	c.209G>T	p.Cys70Phe	missense	Exon 1 of 1	ENSP00000381489.1	Q9BYQ7

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150476 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 75

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150476 Hom.: 0 Cov.: 22 AF XY: 0.0000136 AC XY: 1 AN XY: 73316

African (AFR) AF: 0.0000245 AC: 1 AN: 40786

American (AMR) AF: 0.00 AC: 0 AN: 15106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5080

South Asian (SAS) AF: 0.00 AC: 0 AN: 4664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67666

Other (OTH) AF: 0.00 AC: 0 AN: 2062

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.054	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.89	T
PhyloP100		0.90
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-8.3	D
REVEL	Benign	0.091
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.018	D
Polyphen		0.88	P
Vest4		0.49
MutPred		0.59		Loss of sheet (P = 0.0228)
MVP		0.11
MPC		0.53
ClinPred		0.90	D
GERP RS		3.6
PromoterAI		-0.0046	Neutral
Varity_R		0.53
gMVP		0.066

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74712790; hg19: chr17-39340898;