17-41486433-C-A

Variant names:

• chr17-41486433-C-A
• rs1352124536
• NM_003771.5:c.1347G>T

Variant summary

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

The NM_003771.5(KRT36):​c.1347G>T​(p.Glu449Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: KRT36 NM_003771.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.05
• Publications: 0 publications found

Genes affected

KRT36 (HGNC:6454): (keratin 36) The protein encoded by this gene is a member of the keratin gene family. This type I hair keratin is an acidic protein which heterodimerizes with type II keratins to form hair and nails. The type I hair keratins are clustered in a region of chromosome 17q12-q21 and have the same direction of transcription. [provided by RefSeq, Jul 2008]

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=0.36034924).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003771.5. 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
	KRT36	NM_003771.5	MANE Select	c.1347G>T	p.Glu449Asp	missense	Exon 7 of 7	NP_003762.1	O76013-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT36	ENST00000328119.11	TSL:2 MANE Select	c.1347G>T	p.Glu449Asp	missense	Exon 7 of 7	ENSP00000329165.6	O76013-1
	KRT36	ENST00000393986.2	TSL:1	c.1197G>T	p.Glu399Asp	missense	Exon 8 of 8	ENSP00000377555.2	O76013-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	0.0060	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.37
Sift	Benign	0.12	T
Sift4G	Uncertain	0.057	T
Polyphen		1.0	D
Vest4		0.38
MutPred		0.38		Loss of helix (P = 3e-04)
MVP		0.63
MPC		0.72
ClinPred		0.90	D
GERP RS		4.0
Varity_R		0.076
gMVP		0.65
Mutation Taster		=85/15	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: rs1352124536; hg19: chr17-39642685;