21-30491854-A-C

Variant names:

• chr21-30491854-A-C
• rs1985983591
• NM_181609.4:c.104T>G

Variant summary

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

The NM_181609.4(KRTAP19-3):​c.104T>G​(p.Leu35Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRTAP19-3 NM_181609.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.709
• Publications: 0 publications found

Genes affected

KRTAP19-3 (HGNC:18938): (keratin associated protein 19-3) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000303806 (HGNC:):

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=0.3649218).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181609.4. 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
	KRTAP19-3	NM_181609.4	MANE Select	c.104T>G	p.Leu35Arg	missense	Exon 1 of 1	NP_853640.1	Q7Z4W3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP19-3	ENST00000334063.6	TSL:6 MANE Select	c.104T>G	p.Leu35Arg	missense	Exon 1 of 1	ENSP00000386376.2	Q7Z4W3
	ENSG00000303806	ENST00000797282.1		n.118-7116A>C		intron	N/A
	ENSG00000303806	ENST00000797283.1		n.118-9142A>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 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: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.092
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.71
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.71
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.050
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.23	T
Polyphen		0.44	B
Vest4		0.72
MutPred		0.26		Gain of methylation at L35 (P = 0.0077)
MVP		0.085
MPC		0.049
ClinPred		0.29	T
GERP RS		2.3
PromoterAI		0.012	Neutral
Varity_R		0.44
gMVP		0.064
Mutation Taster		=99/1	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: rs1985983591; hg19: chr21-31864172;