chr17-40750593-T-G

Position:

• chr17-40750593-T-G

Variant summary

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

The NM_181534.4(KRT25):​c.962A>C​(p.His321Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,630 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: KRT25 NM_181534.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.720

Genes affected

KRT25 (HGNC:30839): (keratin 25) 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, Jul 2009]

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/exons	MANE	UniProt
KRT25	NM_181534.4	c.962A>C	p.His321Pro	missense_variant	6/8	ENST00000312150.5
KRT25	XM_011524414.2	c.956A>C	p.His319Pro	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT25	ENST00000312150.5	c.962A>C	p.His321Pro	missense_variant	6/8	1	NM_181534.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461630 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 28, 2022

The c.962A>C (p.H321P) alteration is located in exon 6 (coding exon 6) of the KRT25 gene. This alteration results from a A to C substitution at nucleotide position 962, causing the histidine (H) at amino acid position 321 to be replaced by a proline (P). 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	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.43
Sift	Benign	0.12	T
Sift4G	Benign	0.18	T
Polyphen		0.77	P
Vest4		0.60
MutPred		0.48		Loss of catalytic residue at L323 (P = 0.1197);
MVP		0.74
MPC		0.49
ClinPred		0.62	D
GERP RS		4.4
Varity_R		0.60
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-38906845;