17-41346512-C-G

Variant names:

• chr17-41346512-C-G
• rs142473669
• NM_004138.4:c.1033G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004138.4(KRT33A):​c.1033G>C​(p.Val345Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,916 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: KRT33A NM_004138.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01

Genes affected

KRT33A (HGNC:6450): (keratin 33A) This gene encodes a member of the keratin gene family. This gene is one of multiple type I hair keratin genes that are clustered in a region of chromosome 17q12-q21 and have the same direction of transcription. As a type I hair keratin, the encoded protein is an acidic protein which heterodimerizes with type II keratins to form hair and nails. There are two isoforms of this protein, encoded by two separate genes, keratin 33A and keratin 33B. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT33A	NM_004138.4	c.1033G>C	p.Val345Leu	missense_variant	Exon 6 of 7	ENST00000007735.4	NP_004129.2
KRT33A	XM_011524786.4	c.556G>C	p.Val186Leu	missense_variant	Exon 4 of 5		XP_011523088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT33A	ENST00000007735.4	c.1033G>C	p.Val345Leu	missense_variant	Exon 6 of 7	1	NM_004138.4	ENSP00000007735.3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151916 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151916 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74184

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	0.028
Eigen_PC	Benign	0.020
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.8	M
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.26	B
Vest4		0.43
MutPred		0.76		Gain of disorder (P = 0.0905);
MVP		0.33
MPC		0.40
ClinPred		0.96	D
GERP RS		3.5
Varity_R		0.35
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs142473669; hg19: chr17-39502764;