NM_031960.3:c.224G>T

Variant names:

• chr17-41097861-C-A
• rs781455158
• NM_031960.3:c.224G>T

Variant summary

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

The NM_031960.3(KRTAP4-8):​c.224G>T​(p.Cys75Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000027 in 1,516,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 25)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: KRTAP4-8 NM_031960.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.195
• Publications: 0 publications found

Genes affected

KRTAP4-8 (HGNC:17230): (keratin associated protein 4-8) Involved in aging and hair cycle. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

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=0.38011116).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031960.3. 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
	KRTAP4-8	NM_031960.3	MANE Select	c.224G>T	p.Cys75Phe	missense	Exon 1 of 1	NP_114166.1	Q9BYQ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-8	ENST00000333822.5	TSL:6 MANE Select	c.224G>T	p.Cys75Phe	missense	Exon 1 of 1	ENSP00000328444.4	Q9BYQ9

Frequencies

GnomAD3 genomes AF: 0.0000334 AC: 5 AN: 149764 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000247

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: 0.0000593

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 246694 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000263 AC: 36 AN: 1366272 Hom.: 0 Cov.: 160 AF XY: 0.0000237 AC XY: 16 AN XY: 675430

⚠️ 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: 31824

American (AMR) AF: 0.00 AC: 0 AN: 38936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23798

East Asian (EAS) AF: 0.00 AC: 0 AN: 36794

South Asian (SAS) AF: 0.00 AC: 0 AN: 70454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5040

European-Non Finnish (NFE) AF: 0.0000322 AC: 34 AN: 1055786

Other (OTH) AF: 0.0000359 AC: 2 AN: 55724

⚠️ 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 AF: 0.0000334 AC: 5 AN: 149764 Hom.: 0 Cov.: 25 AF XY: 0.0000137 AC XY: 1 AN XY: 73002

African (AFR) AF: 0.0000247 AC: 1 AN: 40464

American (AMR) AF: 0.00 AC: 0 AN: 15002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000593 AC: 4 AN: 67412

Other (OTH) AF: 0.00 AC: 0 AN: 2036

Alfa AF: 0.0000954 Hom.: 0

ExAC AF: 0.0000659 AC: 6

EpiCase AF: 0.0000546

EpiControl AF: 0.00

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	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	4.7	H
PhyloP100		0.20
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Benign	0.17
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.38
MVP		0.21
MPC		0.14
ClinPred		0.98	D
GERP RS		3.7
PromoterAI		-0.0039	Neutral
Varity_R		0.66
gMVP		0.10

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: rs781455158; hg19: chr17-39254113;