17-41097583-C-T

Variant names:

• chr17-41097583-C-T
• rs72625995
• NM_031960.3:c.502G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031960.3(KRTAP4-8):​c.502G>A​(p.Ala168Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 1,506,894 control chromosomes in the GnomAD database, including 303,204 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A168D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.68 (34562 hom., cov: 28)
  • Exomes 𝑓: 0.62 (268642 hom.)
• Consequence: KRTAP4-8 NM_031960.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0110
• Publications: 15 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.5975036E-7).
• BP6: Variant 17-41097583-C-T is Benign according to our data. Variant chr17-41097583-C-T is described in ClinVar as Benign. ClinVar VariationId is 403023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.853 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP4-8	NM_031960.3	c.502G>A	p.Ala168Thr	missense_variant	Exon 1 of 1	ENST00000333822.5	NP_114166.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP4-8	ENST00000333822.5	c.502G>A	p.Ala168Thr	missense_variant	Exon 1 of 1	6	NM_031960.3	ENSP00000328444.4

Frequencies

GnomAD3 genomes AF: 0.677 AC: 99113 AN: 146298 Hom.: 34519 Cov.: 28

Gnomad AFR AF: 0.861

Gnomad AMI AF: 0.628

Gnomad AMR AF: 0.629

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.497

Gnomad FIN AF: 0.658

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.665

GnomAD2 exomes AF: 0.565 AC: 84691 AN: 150016 AF XY: 0.553

Gnomad AFR exome AF: 0.848

Gnomad AMR exome AF: 0.543

Gnomad ASJ exome AF: 0.630

Gnomad EAS exome AF: 0.363

Gnomad FIN exome AF: 0.651

Gnomad NFE exome AF: 0.580

Gnomad OTH exome AF: 0.582

GnomAD4 exome AF: 0.618 AC: 841204 AN: 1360484 Hom.: 268642 Cov.: 96 AF XY: 0.615 AC XY: 411784 AN XY: 669822

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

African (AFR) AF: 0.869 AC: 22871 AN: 26330

American (AMR) AF: 0.567 AC: 20149 AN: 35520

Ashkenazi Jewish (ASJ) AF: 0.646 AC: 15162 AN: 23462

East Asian (EAS) AF: 0.421 AC: 15569 AN: 36978

South Asian (SAS) AF: 0.514 AC: 39194 AN: 76280

European-Finnish (FIN) AF: 0.660 AC: 32364 AN: 49044

Middle Eastern (MID) AF: 0.703 AC: 3868 AN: 5500

European-Non Finnish (NFE) AF: 0.625 AC: 657428 AN: 1051112

Other (OTH) AF: 0.615 AC: 34599 AN: 56258

⚠️ 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: 0.678 AC: 99203 AN: 146410 Hom.: 34562 Cov.: 28 AF XY: 0.673 AC XY: 48122 AN XY: 71516

African (AFR) AF: 0.860 AC: 31731 AN: 36876

American (AMR) AF: 0.628 AC: 9443 AN: 15032

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 2236 AN: 3458

East Asian (EAS) AF: 0.420 AC: 2154 AN: 5132

South Asian (SAS) AF: 0.496 AC: 2375 AN: 4784

European-Finnish (FIN) AF: 0.658 AC: 6849 AN: 10402

Middle Eastern (MID) AF: 0.694 AC: 197 AN: 284

European-Non Finnish (NFE) AF: 0.627 AC: 42285 AN: 67490

Other (OTH) AF: 0.667 AC: 1364 AN: 2046

Alfa AF: 0.634 Hom.: 5162

Bravo AF: 0.697

ExAC AF: 0.401 AC: 40734

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	14
DANN	Benign	0.81
DEOGEN2	Benign	0.00051	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.0071	T;T
MetaRNN	Benign	6.6e-7	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-2.0	N;.
PhyloP100		-0.011
PrimateAI	Benign	0.31	T
PROVEAN	Benign	2.6	N;.
REVEL	Benign	0.052
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Vest4		0.052
ClinPred		0.0081	T
GERP RS		2.6
Varity_R		0.025
gMVP		0.042
Mutation Taster		=100/0	polymorphism (auto)

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: rs72625995; hg19: chr17-39253835; COSMIC: COSV61563875; COSMIC: COSV61563875;