11-1621907-C-T

Variant names:

• chr11-1621907-C-T
• rs747674556
• NM_001347674.1:c.187G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001347674.1(KRTAP5-4):​c.187G>A​(p.Val63Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,603,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 21)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KRTAP5-4 NM_001347674.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.238
• Publications: 1 publications found

Genes affected

KRTAP5-4 (HGNC:23599): (keratin associated protein 5-4) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10120401).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347674.1. 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
	KRTAP5-4	NM_001347674.1	MANE Select	c.187G>A	p.Val63Met	missense	Exon 1 of 1	NP_001334603.1	A8MUN0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP5-4	ENST00000399682.1	TSL:6 MANE Select	c.187G>A	p.Val63Met	missense	Exon 1 of 1	ENSP00000382590.1	A8MUN0

Frequencies

GnomAD3 genomes AF: 0.0000205 AC: 3 AN: 146448 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000764

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249854 AF XY: 0.0000148

Gnomad AFR exome AF: 0.000191

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457496 Hom.: 0 Cov.: 117 AF XY: 0.00000138 AC XY: 1 AN XY: 725188

African (AFR) AF: 0.00 AC: 0 AN: 33278

American (AMR) AF: 0.0000224 AC: 1 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4482

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110048

Other (OTH) AF: 0.00 AC: 0 AN: 60020

GnomAD4 genome AF: 0.0000205 AC: 3 AN: 146448 Hom.: 0 Cov.: 21 AF XY: 0.0000281 AC XY: 2 AN XY: 71190

African (AFR) AF: 0.0000764 AC: 3 AN: 39276

American (AMR) AF: 0.00 AC: 0 AN: 14634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3426

East Asian (EAS) AF: 0.00 AC: 0 AN: 4760

South Asian (SAS) AF: 0.00 AC: 0 AN: 4460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66880

Other (OTH) AF: 0.00 AC: 0 AN: 2002

Alfa AF: 0.0000540 Hom.: 0

ExAC AF: 0.0000247 AC: 3

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	0.25
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Uncertain	0.99
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.69	D
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.24
PROVEAN	Benign	1.0	N
REVEL	Benign	0.096
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.22	T
Vest4		0.33
MutPred		0.19		Loss of catalytic residue at V63 (P = 0.0814)
MVP		0.29
MPC		0.026
ClinPred		0.19	T
GERP RS		3.3
PromoterAI		-0.0010	Neutral
gMVP		0.038
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs747674556; hg19: chr11-1643137;