17-41084529-C-A

Variant names:

• chr17-41084529-C-A
• rs372960430
• NM_033061.4:c.323C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_033061.4(KRTAP4-7):​c.323C>A​(p.Thr108Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T108A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 4)
  • Exomes 𝑓: 0.000065 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP4-7 NM_033061.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -5.47
• Publications: 11 publications found

Genes affected

KRTAP4-7 (HGNC:18898): (keratin associated protein 4-7) 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, Mar 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0112454295).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033061.4. 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
	KRTAP4-7	NM_033061.4	MANE Select	c.323C>A	p.Thr108Asn	missense	Exon 1 of 1	NP_149050.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-7	ENST00000391417.6	TSL:6 MANE Select	c.323C>A	p.Thr108Asn	missense	Exon 1 of 1	ENSP00000375236.4	Q9BYR0

Frequencies

GnomAD3 genomes AF: 0.000196 AC: 12 AN: 61260 Hom.: 0 Cov.: 4

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000163

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000345

Gnomad SAS AF: 0.000445

Gnomad FIN AF: 0.000262

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000371

Gnomad OTH AF: 0.00121

GnomAD2 exomes AF: 0.00141 AC: 275 AN: 194544 AF XY: 0.00118

Gnomad AFR exome AF: 0.00924

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.000599

Gnomad EAS exome AF: 0.00519

Gnomad FIN exome AF: 0.0000584

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00134

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000653 AC: 76 AN: 1164726 Hom.: 0 Cov.: 97 AF XY: 0.0000448 AC XY: 26 AN XY: 580054

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00206 AC: 53 AN: 25734

American (AMR) AF: 0.000111 AC: 4 AN: 36042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19180

East Asian (EAS) AF: 0.00 AC: 0 AN: 33146

South Asian (SAS) AF: 0.0000136 AC: 1 AN: 73328

European-Finnish (FIN) AF: 0.000121 AC: 4 AN: 33178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3648

European-Non Finnish (NFE) AF: 0.00000783 AC: 7 AN: 893650

Other (OTH) AF: 0.000150 AC: 7 AN: 46820

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000196 AC: 12 AN: 61344 Hom.: 0 Cov.: 4 AF XY: 0.000266 AC XY: 8 AN XY: 30078

African (AFR) AF: 0.000361 AC: 6 AN: 16600

American (AMR) AF: 0.000163 AC: 1 AN: 6152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1362

East Asian (EAS) AF: 0.000346 AC: 1 AN: 2894

South Asian (SAS) AF: 0.000446 AC: 1 AN: 2242

European-Finnish (FIN) AF: 0.000262 AC: 1 AN: 3818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 96

European-Non Finnish (NFE) AF: 0.0000371 AC: 1 AN: 26984

Other (OTH) AF: 0.00119 AC: 1 AN: 838

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.000275 AC: 33

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	0.11
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.1
DANN	Benign	0.94
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.022	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.93	T
PhyloP100		-5.5
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.013
Sift	Benign	0.037	D
Sift4G	Uncertain	0.051	T
Vest4		0.20
MutPred		0.36		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.048
MPC		0.037
ClinPred		0.0070	T
GERP RS		1.0
PromoterAI		0.016	Neutral
gMVP		0.097
Mutation Taster		=98/2	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: rs372960430; hg19: chr17-39240781; COSMIC: COSV66951555;