17-40700369-C-A

Position:

• chr17-40700369-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019016.3(KRT24):​c.870G>T​(p.Met290Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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)
• Consequence: KRT24 NM_019016.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.157

Genes affected

KRT24 (HGNC:18527): (keratin 24) This gene encodes a member of the type I (acidic) keratin family, which belongs to the superfamily of intermediate filament (IF) proteins. Keratins are heteropolymeric structural proteins which form the intermediate filament. These filaments, along with actin microfilaments and microtubules, compose the cytoskeleton of epithelial cells. The type I keratin genes are clustered in a region of chromosome 17q12-q21. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14076367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT24	NM_019016.3	c.870G>T	p.Met290Ile	missense_variant	4/8	ENST00000264651.3	NP_061889.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT24	ENST00000264651.3	c.870G>T	p.Met290Ile	missense_variant	4/8	1	NM_019016.3	ENSP00000264651	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250016 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135212

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2022

The c.870G>T (p.M290I) alteration is located in exon 4 (coding exon 4) of the KRT24 gene. This alteration results from a G to T substitution at nucleotide position 870, causing the methionine (M) at amino acid position 290 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.83
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.93	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.22
Sift	Benign	0.068	T
Sift4G	Benign	0.084	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.51		Gain of catalytic residue at M290 (P = 0.0884);
MVP		0.19
MPC		0.078
ClinPred		0.033	T
GERP RS		3.9
Varity_R		0.18
gMVP		0.41

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: rs776464675; hg19: chr17-38856621;