21-30755305-C-T

Variant names:

• chr21-30755305-C-T
• rs147233060
• NM_181619.2:c.74G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_181619.2(KRTAP21-1):​c.74G>A​(p.Gly25Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000713 in 1,613,342 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (1 hom.)
• Consequence: KRTAP21-1 NM_181619.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.611

Genes affected

KRTAP21-1 (HGNC:18945): (keratin associated protein 21-1) Predicted to be involved in hair follicle development. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.129177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP21-1	NM_181619.2	c.74G>A	p.Gly25Asp	missense_variant	Exon 1 of 1	ENST00000335093.5	NP_853650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP21-1	ENST00000335093.5	c.74G>A	p.Gly25Asp	missense_variant	Exon 1 of 1	6	NM_181619.2	ENSP00000335566.3

Frequencies

GnomAD3 genomes AF: 0.000382 AC: 58 AN: 152030 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

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: 0.000706

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000304 AC: 76 AN: 250336 Hom.: 0 AF XY: 0.000244 AC XY: 33 AN XY: 135314

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000559

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000748 AC: 1093 AN: 1461312 Hom.: 1 Cov.: 31 AF XY: 0.000703 AC XY: 511 AN XY: 726882

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000949

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000382 AC: 58 AN: 152030 Hom.: 1 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74242

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000557 Hom.: 0

Bravo AF: 0.000457

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00182 AC: 7

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.00104

EpiControl AF: 0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.74G>A (p.G25D) alteration is located in exon 1 (coding exon 1) of the KRTAP21-1 gene. This alteration results from a G to A substitution at nucleotide position 74, causing the glycine (G) at amino acid position 25 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	6.6
DANN	Benign	0.50
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.053
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.96	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.30
Sift	Benign	0.74	T
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.33
MVP		0.18
MPC		0.031
ClinPred		0.11	T
GERP RS		4.1
Varity_R		0.12
gMVP		0.067

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs147233060; hg19: chr21-32127623; COSMIC: COSV58646756;