12-52839127-A-T

Position:

• chr12-52839127-A-T

Variant summary

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

The NM_173352.4(KRT78):​c.1549T>A​(p.Ser517Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRT78 NM_173352.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81

Genes affected

KRT78 (HGNC:28926): (keratin 78) This gene is a member of the type II keratin gene family and encodes a protein with an intermediate filament domain. Keratins are the major structural proteins in epithelial cells, forming a cytoplasmic network of 10 to 12 nm wide intermediate filaments and creating a scaffold that gives cells the ability to withstand mechanical and non-mechanical stresses. The genes of the type II keratin family are located as a gene cluster at 12p13.13. Four pseudogenes of this gene family have been identified. [provided by RefSeq, Jul 2008]

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=0.2129859).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT78	NM_173352.4	c.1549T>A	p.Ser517Thr	missense_variant	9/9	ENST00000304620.5	NP_775487.2
KRT78	NM_001300814.1	c.1219T>A	p.Ser407Thr	missense_variant	9/9		NP_001287743.1
KRT78	XM_011538010.2	c.1453T>A	p.Ser485Thr	missense_variant	8/8		XP_011536312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT78	ENST00000304620.5	c.1549T>A	p.Ser517Thr	missense_variant	9/9	1	NM_173352.4	ENSP00000306261.4
KRT78	ENST00000359499.8	c.1219T>A	p.Ser407Thr	missense_variant	9/9	1		ENSP00000352479.4
KRT78	ENST00000547920.1	c.*173T>A		3_prime_UTR_variant	2/2	3		ENSP00000448562.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460846 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726614

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

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

Jul 25, 2024

The c.1549T>A (p.S517T) alteration is located in exon 9 (coding exon 9) of the KRT78 gene. This alteration results from a T to A substitution at nucleotide position 1549, causing the serine (S) at amino acid position 517 to be replaced by a threonine (T). 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	0.10
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.0014	.;T
Eigen	Benign	-0.025
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.1	.;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.079	T;T
Polyphen		0.99	.;D
Vest4		0.34
MutPred		0.16		.;Gain of relative solvent accessibility (P = 0.0215);
MVP		0.57
MPC		0.17
ClinPred		0.77	D
GERP RS		3.9
Varity_R		0.19
gMVP		0.33

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-53232911;