NM_181607.3:c.229C>T

Variant names:

• chr21-30480089-G-A
• rs779790994
• NM_181607.3:c.229C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_181607.3(KRTAP19-1):​c.229C>T​(p.Arg77Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R77G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: KRTAP19-1 NM_181607.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.243
• Publications: 8 publications found

Genes affected

KRTAP19-1 (HGNC:18936): (keratin associated protein 19-1) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000303806 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05449468).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181607.3. 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
	KRTAP19-1	NM_181607.3	MANE Select	c.229C>T	p.Arg77Cys	missense	Exon 1 of 1	NP_853638.1	Q8IUB9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP19-1	ENST00000390689.3	TSL:6 MANE Select	c.229C>T	p.Arg77Cys	missense	Exon 1 of 1	ENSP00000375108.2	Q8IUB9
	ENSG00000303806	ENST00000797282.1		n.117+4145G>A		intron	N/A
	ENSG00000303806	ENST00000797283.1		n.117+4145G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152090 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251360 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727222

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111998

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152090 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74294

African (AFR) AF: 0.0000966 AC: 4 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.48
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.038	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.24
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.039
Sift4G	Benign	0.19	T
Polyphen		0.017	B
Vest4		0.18
MutPred		0.17		Loss of methylation at R77 (P = 0.0339)
MVP		0.048
MPC		0.16
ClinPred		0.17	T
GERP RS		0.75
PromoterAI		-0.0024	Neutral
Varity_R		0.37
gMVP		0.050
Mutation Taster		=100/0	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: rs779790994; hg19: chr21-31852408; COSMIC: COSV66861263;