rs3657

Variant names:

• chr12-52286224-T-C
• rs3657
• NM_002281.4:c.*31A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-52286224-T-C
• chr12-52286224-T-A
• chr12-52286224-T-G

Variant summary

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

The NM_002281.4(KRT81):​c.*31A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 1,534,656 control chromosomes in the GnomAD database, including 198,728 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18135 hom., cov: 33)
  • Exomes 𝑓: 0.51 (180593 hom.)
• Consequence: KRT81 NM_002281.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.71
• Publications: 8 publications found

Genes affected

KRT81 (HGNC:6458): (keratin 81) The protein encoded by this gene is a member of the keratin gene family. As a type II hair keratin, it is a basic protein which heterodimerizes with type I keratins to form hair and nails. The type II hair keratins are clustered in a region of chromosome 12q13 and are grouped into two distinct subfamilies based on structure similarity. One subfamily, consisting of KRTHB1, KRTHB3, and KRTHB6, is highly related. The other less-related subfamily includes KRTHB2, KRTHB4, and KRTHB5. All hair keratins are expressed in the hair follicle; this hair keratin, as well as KRTHB3 and KRTHB6, is found primarily in the hair cortex. Mutations in this gene and KRTHB6 have been observed in patients with a rare dominant hair disease, monilethrix. Some human genome assemblies (example T2T-CHM13) have a non-coding version of the gene due to the presence of a SNP that introduces a premature stop codon after codon 281. [provided by RefSeq, Jan 2024]

KRT86 (HGNC:6463): (keratin 86) This gene encodes a type II keratin protein, which heterodimerizes with type I keratins to form hair and nails. This gene is present in a cluster of related genes and pseudogenes on chromosome 12. Mutations in this gene have been observed in patients with the hair disease monilethrix. [provided by RefSeq, Feb 2016]

KRT86 Gene-Disease associations (from GenCC):

• monilethrix

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet
• monilethrix-1

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-52286224-T-C is Benign according to our data. Variant chr12-52286224-T-C is described in ClinVar as Benign. ClinVar VariationId is 1273289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002281.4. 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
	KRT81	NM_002281.4	MANE Select	c.*31A>G		3_prime_UTR	Exon 9 of 9	NP_002272.2	Q14533
	KRT86	NM_001320198.2	MANE Select	c.-5+10278T>C		intron	N/A	NP_001307127.1	O43790

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT81	ENST00000327741.9	TSL:1 MANE Select	c.*31A>G		3_prime_UTR	Exon 9 of 9	ENSP00000369349.4	Q14533
	KRT86	ENST00000423955.7	TSL:2 MANE Select	c.-5+10278T>C		intron	N/A	ENSP00000444533.1	O43790
	KRT86	ENST00000958042.1		c.-5+7540T>C		intron	N/A	ENSP00000628101.1

Frequencies

GnomAD3 genomes AF: 0.484 AC: 73473 AN: 151894 Hom.: 18127 Cov.: 33

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.747

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.474

GnomAD2 exomes AF: 0.442 AC: 67696 AN: 153324 AF XY: 0.445

Gnomad AFR exome AF: 0.473

Gnomad AMR exome AF: 0.307

Gnomad ASJ exome AF: 0.457

Gnomad EAS exome AF: 0.197

Gnomad FIN exome AF: 0.530

Gnomad NFE exome AF: 0.523

Gnomad OTH exome AF: 0.459

GnomAD4 exome AF: 0.506 AC: 699278 AN: 1382644 Hom.: 180593 Cov.: 26 AF XY: 0.503 AC XY: 343819 AN XY: 683094

African (AFR) AF: 0.476 AC: 14952 AN: 31442

American (AMR) AF: 0.321 AC: 11528 AN: 35960

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 11542 AN: 25078

East Asian (EAS) AF: 0.212 AC: 7657 AN: 36150

South Asian (SAS) AF: 0.433 AC: 34179 AN: 78896

European-Finnish (FIN) AF: 0.531 AC: 26013 AN: 48954

Middle Eastern (MID) AF: 0.422 AC: 2001 AN: 4740

European-Non Finnish (NFE) AF: 0.529 AC: 563330 AN: 1064002

Other (OTH) AF: 0.489 AC: 28076 AN: 57422

GnomAD4 genome AF: 0.484 AC: 73505 AN: 152012 Hom.: 18135 Cov.: 33 AF XY: 0.481 AC XY: 35712 AN XY: 74282

African (AFR) AF: 0.477 AC: 19771 AN: 41446

American (AMR) AF: 0.398 AC: 6084 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 1572 AN: 3470

East Asian (EAS) AF: 0.202 AC: 1041 AN: 5166

South Asian (SAS) AF: 0.427 AC: 2057 AN: 4816

European-Finnish (FIN) AF: 0.532 AC: 5627 AN: 10580

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.523 AC: 35549 AN: 67932

Other (OTH) AF: 0.474 AC: 1001 AN: 2112

Alfa AF: 0.494 Hom.: 11016

Bravo AF: 0.472

Asia WGS AF: 0.366 AC: 1276 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.26
DANN	Benign	0.50
PhyloP100		-2.7
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: rs3657; hg19: chr12-52680008; COSMIC: COSV59810361; COSMIC: COSV59810361;