12-52233347-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005556.4(KRT7):c.51C>A(p.Phe17Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,572,192 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (20 hom.)
• Consequence: KRT7 NM_005556.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.566

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022589564).
• BP6: Variant 12-52233347-C-A is Benign according to our data. Variant chr12-52233347-C-A is described in ClinVar as [Benign]. Clinvar id is 769820.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00151 (2140/1419892) while in subpopulation AMR AF= 0.0228 (867/38008). AF 95% confidence interval is 0.0216. There are 20 homozygotes in gnomad4_exome. There are 943 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT7	NM_005556.4	c.51C>A	p.Phe17Leu	missense_variant	1/9	ENST00000331817.6
KRT7	XM_011538325.3	c.51C>A	p.Phe17Leu	missense_variant	1/8
KRT7	XM_047428827.1	c.51C>A	p.Phe17Leu	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT7	ENST00000331817.6	c.51C>A	p.Phe17Leu	missense_variant	1/9	1	NM_005556.4	P1
KRT7	ENST00000546666.1	n.199C>A		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 336 AN: 152188 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00811

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00829

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00639 AC: 1241 AN: 194104 Hom.: 12 AF XY: 0.00499 AC XY: 541 AN XY: 108516

Gnomad AFR exome AF: 0.000324

Gnomad AMR exome AF: 0.0266

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0154

Gnomad SAS exome AF: 0.000195

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.000667

Gnomad OTH exome AF: 0.00874

GnomAD4 exome AF: 0.00151 AC: 2140 AN: 1419892 Hom.: 20 Cov.: 31 AF XY: 0.00134 AC XY: 943 AN XY: 706200

Gnomad4 AFR exome AF: 0.0000692

Gnomad4 AMR exome AF: 0.0228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0119

Gnomad4 SAS exome AF: 0.000306

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.000140

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00222 AC: 338 AN: 152300 Hom.: 8 Cov.: 33 AF XY: 0.00242 AC XY: 180 AN XY: 74468

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00823

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0142

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00829

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00108 Hom.: 1

Bravo AF: 0.00297

ESP6500AA AF: 0.000456 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00505 AC: 609

Asia WGS AF: 0.00260 AC: 9 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 22, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	7.0
Dann	Benign	0.62
DEOGEN2	Benign	0.083	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.29
Sift	Benign	0.61	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.037
MutPred		0.21		Gain of MoRF binding (P = 0.0951);
MVP		0.18
MPC		0.32
ClinPred		0.0034	T
GERP RS		-0.85
Varity_R		0.037
gMVP		0.36

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: rs145797078; hg19: chr12-52627131;