rs3826549

Variant names:

• chr17-41586466-A-G
• rs3826549
• NM_000526.5:c.369T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-41586466-A-G
• chr17-41586466-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000526.5(KRT14):​c.369T>C​(p.Asn123Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.585 in 1,613,754 control chromosomes in the GnomAD database, including 283,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25950 hom., cov: 31)
  • Exomes 𝑓: 0.59 (257118 hom.)
• Consequence: KRT14 NM_000526.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -0.276
• Publications: 17 publications found

Genes affected

KRT14 (HGNC:6416): (keratin 14) This gene encodes a member of the keratin family, the most diverse group of intermediate filaments. This gene product, a type I keratin, is usually found as a heterotetramer with two keratin 5 molecules, a type II keratin. Together they form the cytoskeleton of epithelial cells. Mutations in the genes for these keratins are associated with epidermolysis bullosa simplex. At least one pseudogene has been identified at 17p12-p11. [provided by RefSeq, Jul 2008]

KRT14 Gene-Disease associations (from GenCC):

• epidermolysis bullosa simplex 1A, generalized severe

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet
• Naegeli-Franceschetti-Jadassohn syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet, Genomics England PanelApp
• epidermolysis bullosa simplex

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, Orphanet
• dermatopathia pigmentosa reticularis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• epidermolysis bullosa simplex 1B, generalized intermediate

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• epidermolysis bullosa simplex 1C, localized

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• epidermolysis bullosa simplex 2F, with mottled pigmentation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 17-41586466-A-G is Benign according to our data. Variant chr17-41586466-A-G is described in ClinVar as Benign. ClinVar VariationId is 66346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.276 with no splicing effect.
• 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_000526.5. 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
	KRT14	NM_000526.5	MANE Select	c.369T>C	p.Asn123Asn	synonymous	Exon 1 of 8	NP_000517.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT14	ENST00000167586.7	TSL:1 MANE Select	c.369T>C	p.Asn123Asn	synonymous	Exon 1 of 8	ENSP00000167586.6	P02533

Frequencies

GnomAD3 genomes AF: 0.575 AC: 87247 AN: 151762 Hom.: 25934 Cov.: 31

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.780

Gnomad AMR AF: 0.676

Gnomad ASJ AF: 0.562

Gnomad EAS AF: 0.948

Gnomad SAS AF: 0.736

Gnomad FIN AF: 0.658

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.560

Gnomad OTH AF: 0.560

GnomAD2 exomes AF: 0.644 AC: 161967 AN: 251458 AF XY: 0.641

Gnomad AFR exome AF: 0.476

Gnomad AMR exome AF: 0.777

Gnomad ASJ exome AF: 0.561

Gnomad EAS exome AF: 0.945

Gnomad FIN exome AF: 0.666

Gnomad NFE exome AF: 0.565

Gnomad OTH exome AF: 0.596

GnomAD4 exome AF: 0.586 AC: 857284 AN: 1461874 Hom.: 257118 Cov.: 93 AF XY: 0.590 AC XY: 428742 AN XY: 727232

African (AFR) AF: 0.472 AC: 15803 AN: 33480

American (AMR) AF: 0.764 AC: 34163 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 14714 AN: 26136

East Asian (EAS) AF: 0.959 AC: 38083 AN: 39700

South Asian (SAS) AF: 0.716 AC: 61718 AN: 86256

European-Finnish (FIN) AF: 0.665 AC: 35533 AN: 53420

Middle Eastern (MID) AF: 0.506 AC: 2915 AN: 5766

European-Non Finnish (NFE) AF: 0.557 AC: 619023 AN: 1112002

Other (OTH) AF: 0.585 AC: 35332 AN: 60390

GnomAD4 genome AF: 0.575 AC: 87307 AN: 151880 Hom.: 25950 Cov.: 31 AF XY: 0.584 AC XY: 43331 AN XY: 74242

African (AFR) AF: 0.473 AC: 19564 AN: 41394

American (AMR) AF: 0.677 AC: 10340 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.562 AC: 1947 AN: 3466

East Asian (EAS) AF: 0.948 AC: 4873 AN: 5140

South Asian (SAS) AF: 0.735 AC: 3539 AN: 4812

European-Finnish (FIN) AF: 0.658 AC: 6969 AN: 10584

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.560 AC: 38045 AN: 67896

Other (OTH) AF: 0.564 AC: 1189 AN: 2108

Alfa AF: 0.557 Hom.: 10161

Bravo AF: 0.573

EpiCase AF: 0.547

EpiControl AF: 0.556

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	1	Epidermolysis bullosa simplex 1A, generalized severe;C0080333:Epidermolysis bullosa simplex 1C, localized;C0343111:Naegeli-Franceschetti-Jadassohn syndrome;C0406778:Dermatopathia pigmentosa reticularis;C3715082:Epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive;C5561924:Epidermolysis bullosa simplex, Koebner type (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.8
DANN	Benign	0.57
PhyloP100		-0.28
PromoterAI		0.029	Neutral
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3826549; hg19: chr17-39742718; COSMIC: COSV51423085; COSMIC: COSV51423085;