17-41364951-A-T

Variant names:

• chr17-41364951-A-T
• rs779806045
• NM_002279.5:c.925T>A

Variant summary

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

The NM_002279.5(KRT33B):​c.925T>A​(p.Ser309Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000066 in 151,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S309A) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: KRT33B NM_002279.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0810
• Publications: 0 publications found

Genes affected

KRT33B (HGNC:6451): (keratin 33B) 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

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=0.04635787).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002279.5. 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
	KRT33B	NM_002279.5	MANE Select	c.925T>A	p.Ser309Thr	missense	Exon 6 of 7	NP_002270.1	Q14525

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT33B	ENST00000251646.8	TSL:1 MANE Select	c.925T>A	p.Ser309Thr	missense	Exon 6 of 7	ENSP00000251646.3	Q14525

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151492 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000245

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

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151492 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73986

African (AFR) AF: 0.0000245 AC: 1 AN: 40770

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.74
DEOGEN2	Benign	0.093	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.041	N
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.86	L
PhyloP100		-0.081
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.16
Sift	Benign	0.57	T
Sift4G	Benign	0.74	T
Polyphen		0.022	B
Vest4		0.21
MutPred		0.40		Loss of phosphorylation at S309 (P = 0.0474)
MVP		0.29
MPC		0.35
ClinPred		0.086	T
GERP RS		1.2
Varity_R		0.077
gMVP		0.17

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: rs779806045; hg19: chr17-39521203;