NM_000226.4:c.1395-45A>G

Variant names:

• chr17-41567795-T-C
• rs1008753
• NM_000226.4:c.1395-45A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000226.4(KRT9):​c.1395-45A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,612,090 control chromosomes in the GnomAD database, including 279,031 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25232 hom., cov: 32)
  • Exomes 𝑓: 0.58 (253799 hom.)
• Consequence: KRT9 NM_000226.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.692
• Publications: 13 publications found

Genes affected

KRT9 (HGNC:6447): (keratin 9) This gene encodes the type I keratin 9, an intermediate filament chain expressed only in the terminally differentiated epidermis of palms and soles. Mutations in this gene cause epidermolytic palmoplantar keratoderma. [provided by RefSeq, Jul 2008]

KRT9 Gene-Disease associations (from GenCC):

• epidermolytic palmoplantar keratoderma, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-41567795-T-C is Benign according to our data. Variant chr17-41567795-T-C is described in ClinVar as Benign. ClinVar VariationId is 1283937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000226.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT9	NM_000226.4	MANE Select	c.1395-45A>G		intron	N/A	NP_000217.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT9	ENST00000246662.9	TSL:1 MANE Select	c.1395-45A>G		intron	N/A	ENSP00000246662.4
	KRT9	ENST00000588431.1	TSL:1	c.696-45A>G		intron	N/A	ENSP00000467932.1

Frequencies

GnomAD3 genomes AF: 0.566 AC: 85982 AN: 152008 Hom.: 25217 Cov.: 32

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.769

Gnomad AMR AF: 0.665

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.948

Gnomad SAS AF: 0.721

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.549

GnomAD2 exomes AF: 0.640 AC: 157397 AN: 245974 AF XY: 0.636

Gnomad AFR exome AF: 0.455

Gnomad AMR exome AF: 0.775

Gnomad ASJ exome AF: 0.586

Gnomad EAS exome AF: 0.942

Gnomad FIN exome AF: 0.663

Gnomad NFE exome AF: 0.560

Gnomad OTH exome AF: 0.598

GnomAD4 exome AF: 0.583 AC: 851100 AN: 1459962 Hom.: 253799 Cov.: 59 AF XY: 0.586 AC XY: 425512 AN XY: 726434

African (AFR) AF: 0.449 AC: 15041 AN: 33474

American (AMR) AF: 0.760 AC: 34003 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 15346 AN: 26114

East Asian (EAS) AF: 0.957 AC: 38002 AN: 39698

South Asian (SAS) AF: 0.697 AC: 60114 AN: 86240

European-Finnish (FIN) AF: 0.657 AC: 34070 AN: 51820

Middle Eastern (MID) AF: 0.496 AC: 2860 AN: 5764

European-Non Finnish (NFE) AF: 0.555 AC: 616559 AN: 1111778

Other (OTH) AF: 0.582 AC: 35105 AN: 60356

GnomAD4 genome AF: 0.566 AC: 86042 AN: 152128 Hom.: 25232 Cov.: 32 AF XY: 0.575 AC XY: 42741 AN XY: 74362

African (AFR) AF: 0.453 AC: 18785 AN: 41476

American (AMR) AF: 0.665 AC: 10175 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2044 AN: 3472

East Asian (EAS) AF: 0.948 AC: 4911 AN: 5178

South Asian (SAS) AF: 0.720 AC: 3477 AN: 4830

European-Finnish (FIN) AF: 0.653 AC: 6908 AN: 10584

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.555 AC: 37750 AN: 67980

Other (OTH) AF: 0.551 AC: 1164 AN: 2112

Alfa AF: 0.554 Hom.: 38509

Bravo AF: 0.563

Asia WGS AF: 0.805 AC: 2798 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.33
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism (auto)

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: rs1008753; hg19: chr17-39724047;