chr12-52245598-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005556.4(KRT7):ā€‹c.1171A>Gā€‹(p.Thr391Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.000061 ( 0 hom. )

Consequence

KRT7
NM_005556.4 missense

Scores

6
10
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.22
Variant links:
Genes affected
KRT7 (HGNC:6445): (keratin 7) The protein encoded by this gene is a member of the keratin gene family. The type II cytokeratins 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 type II cytokeratin is specifically expressed in the simple epithelia lining the cavities of the internal organs and in the gland ducts and blood vessels. The genes encoding the type II cytokeratins are clustered in a region of chromosome 12q12-q13. Alternative splicing may result in several transcript variants; however, not all variants have been fully described. [provided by RefSeq, Jul 2008]
KRT7-AS (HGNC:52643): (KRT7 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KRT7NM_005556.4 linkuse as main transcriptc.1171A>G p.Thr391Ala missense_variant 7/9 ENST00000331817.6
KRT7-ASNR_146274.1 linkuse as main transcriptn.1143T>C non_coding_transcript_exon_variant 2/2
KRT7XM_011538325.3 linkuse as main transcriptc.1171A>G p.Thr391Ala missense_variant 7/8
KRT7XM_017019294.2 linkuse as main transcriptc.640A>G p.Thr214Ala missense_variant 5/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KRT7ENST00000331817.6 linkuse as main transcriptc.1171A>G p.Thr391Ala missense_variant 7/91 NM_005556.4 P1
KRT7-ASENST00000546686.1 linkuse as main transcriptn.1143T>C non_coding_transcript_exon_variant 2/21

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152226
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251172
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135782
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000609
AC:
89
AN:
1461528
Hom.:
0
Cov.:
33
AF XY:
0.0000633
AC XY:
46
AN XY:
727056
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000692
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152226
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 27, 2024The c.1171A>G (p.T391A) alteration is located in exon 7 (coding exon 7) of the KRT7 gene. This alteration results from a A to G substitution at nucleotide position 1171, causing the threonine (T) at amino acid position 391 to be replaced by an alanine (A). 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
0.13
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Pathogenic
0.22
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.59
D
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.77
T
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.92
D
MetaSVM
Uncertain
0.54
D
MutationAssessor
Uncertain
2.8
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.57
T
PROVEAN
Pathogenic
-4.7
D
REVEL
Pathogenic
0.80
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0060
D
Polyphen
1.0
D
Vest4
0.77
MutPred
0.75
Loss of phosphorylation at T391 (P = 0.0525);
MVP
0.85
MPC
0.96
ClinPred
0.92
D
GERP RS
3.3
Varity_R
0.64
gMVP
0.85

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs773204229; hg19: chr12-52639382; API