17-41084529-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_033061.4(KRTAP4-7):​c.323C>G​(p.Thr108Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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 0.000033 (0 hom., cov: 4)
  • Exomes 𝑓: 0.000018 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP4-7 NM_033061.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.069031805).

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>G	p.Thr108Ser	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>G	p.Thr108Ser	missense	Exon 1 of 1	ENSP00000375236.4	Q9BYR0

Frequencies

GnomAD3 genomes AF: 0.0000326 AC: 2 AN: 61298 Hom.: 0 Cov.: 4

Gnomad AFR AF: 0.0000604

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: 0.0000371

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000103 AC: 2 AN: 194544 AF XY: 0.0000188

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000683

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000180 AC: 21 AN: 1164668 Hom.: 1 Cov.: 97 AF XY: 0.0000259 AC XY: 15 AN XY: 580018

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

African (AFR) AF: 0.00 AC: 0 AN: 25774

American (AMR) AF: 0.0000277 AC: 1 AN: 36048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19178

East Asian (EAS) AF: 0.000121 AC: 4 AN: 33144

South Asian (SAS) AF: 0.0000273 AC: 2 AN: 73330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3646

European-Non Finnish (NFE) AF: 0.0000134 AC: 12 AN: 893548

Other (OTH) AF: 0.0000427 AC: 2 AN: 46824

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000942886), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000326 AC: 2 AN: 61382 Hom.: 0 Cov.: 4 AF XY: 0.0000664 AC XY: 2 AN XY: 30100

African (AFR) AF: 0.0000602 AC: 1 AN: 16620

American (AMR) AF: 0.00 AC: 0 AN: 6168

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 2894

South Asian (SAS) AF: 0.00 AC: 0 AN: 2242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3820

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

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

Other (OTH) AF: 0.00 AC: 0 AN: 838

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000834 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.028
DANN	Benign	0.74
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.075	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.98	T
PhyloP100		-5.5
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.014
Sift	Benign	0.59	T
Sift4G	Benign	0.72	T
Vest4		0.049
MutPred		0.36		Gain of glycosylation at T108 (P = 0.0957)
MVP		0.085
MPC		0.032
ClinPred		0.024	T
GERP RS		1.0
PromoterAI		0.026	Neutral
gMVP		0.079
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;