17-40751280-T-G

Position:

• chr17-40751280-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_181534.4(KRT25):​c.716A>C​(p.Glu239Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00404 in 1,614,066 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (76 hom.)
• Consequence: KRT25 NM_181534.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.60

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 Benign. Variant got -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.014849842).
• BP6: Variant 17-40751280-T-G is Benign according to our data. Variant chr17-40751280-T-G is described in ClinVar as [Benign]. Clinvar id is 715041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00323 (492/152360) while in subpopulation SAS AF= 0.0259 (125/4832). AF 95% confidence interval is 0.0222. There are 8 homozygotes in gnomad4. There are 246 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT25	NM_181534.4	c.716A>C	p.Glu239Ala	missense_variant	4/8	ENST00000312150.5	NP_853512.1
KRT25	XM_011524414.2	c.710A>C	p.Glu237Ala	missense_variant	5/9		XP_011522716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT25	ENST00000312150.5	c.716A>C	p.Glu239Ala	missense_variant	4/8	1	NM_181534.4	ENSP00000310573	P1

Frequencies

GnomAD3 genomes AF: 0.00326 AC: 496 AN: 152242 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00646 AC: 1621 AN: 250936 Hom.: 28 AF XY: 0.00795 AC XY: 1078 AN XY: 135608

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00235

Gnomad ASJ exome AF: 0.0214

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0298

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00320

Gnomad OTH exome AF: 0.00621

GnomAD4 exome AF: 0.00412 AC: 6026 AN: 1461706 Hom.: 76 Cov.: 32 AF XY: 0.00502 AC XY: 3652 AN XY: 727164

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.00269

Gnomad4 ASJ exome AF: 0.0212

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0281

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00216

Gnomad4 OTH exome AF: 0.00674

GnomAD4 genome AF: 0.00323 AC: 492 AN: 152360 Hom.: 8 Cov.: 32 AF XY: 0.00330 AC XY: 246 AN XY: 74512

Gnomad4 AFR AF: 0.000745

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.0210

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0259

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00290

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.0249 Hom.: 2350

Bravo AF: 0.00266

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00647 AC: 786

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00456

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.015	T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.78
MVP		0.91
MPC		0.36
ClinPred		0.028	T
GERP RS		5.7
Varity_R		0.73
gMVP		0.59

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: rs140952603; hg19: chr17-38907532;