12-52590913-G-A

Position:

• chr12-52590913-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000293745.7(KRT72):​c.1012C>T​(p.Leu338Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,455,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KRT72 ENST00000293745.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.270

Genes affected

KRT72 (HGNC:28932): (keratin 72) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells. The type II keratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This gene encodes a type II keratin that is specifically expressed in the inner root sheath of hair follicles. The type II keratins are clustered in a region of chromosome 12q12-q13. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06832811).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT72	NM_080747.3	c.1012C>T	p.Leu338Phe	missense_variant	6/9	ENST00000293745.7	NP_542785.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT72	ENST00000293745.7	c.1012C>T	p.Leu338Phe	missense_variant	6/9	1	NM_080747.3	ENSP00000293745	P1
KRT72	ENST00000537672.6	c.1012C>T	p.Leu338Phe	missense_variant	6/10	2		ENSP00000441160	P1
KRT72	ENST00000354310.4	c.963+551C>T		intron_variant		2		ENSP00000346269
KRT72	ENST00000550829.1	c.*701C>T		3_prime_UTR_variant, NMD_transcript_variant	7/10	2		ENSP00000446881

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1455686 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723578

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000271

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

Oct 26, 2022

The c.1012C>T (p.L338F) alteration is located in exon 6 (coding exon 6) of the KRT72 gene. This alteration results from a C to T substitution at nucleotide position 1012, causing the leucine (L) at amino acid position 338 to be replaced by a phenylalanine (F). 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	Benign	0.086
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.22	.;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.070	N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.15	T;T
Polyphen		0.44	B;B
Vest4		0.060
MutPred		0.43		Gain of catalytic residue at K340 (P = 0.0188);Gain of catalytic residue at K340 (P = 0.0188);
MVP		0.47
MPC		0.052
ClinPred		0.29	T
GERP RS		1.3
Varity_R		0.17
gMVP		0.27

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: rs1939984840; hg19: chr12-52984697;