12-52567045-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_175053.4(KRT74):c.1514C>T(p.Ala505Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,598,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A505A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: KRT74 NM_175053.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.769

Genes affected

KRT74 (HGNC:28929): (keratin 74) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins. This protein belongs to a family of keratins that are specifically expressed in the inner root sheath of hair follicles.[provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008202374).
• BP6: Variant 12-52567045-G-A is Benign according to our data. Variant chr12-52567045-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1099347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT74	NM_175053.4	c.1514C>T	p.Ala505Val	missense_variant	9/9	ENST00000305620.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT74	ENST00000305620.3	c.1514C>T	p.Ala505Val	missense_variant	9/9	1	NM_175053.4	P1
KRT74	ENST00000549343.5	c.1556C>T	p.Ala519Val	missense_variant	10/10	5
KRT74	ENST00000546384.1	n.501C>T		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000146 AC: 35 AN: 240424 Hom.: 0 AF XY: 0.000138 AC XY: 18 AN XY: 130002

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.000301

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00116

Gnomad SAS exome AF: 0.0000347

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000927

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.0000650 AC: 94 AN: 1446734 Hom.: 0 Cov.: 30 AF XY: 0.0000669 AC XY: 48 AN XY: 717628

Gnomad4 AFR exome AF: 0.0000905

Gnomad4 AMR exome AF: 0.000229

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000837

Gnomad4 SAS exome AF: 0.0000237

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000299

Gnomad4 OTH exome AF: 0.000218

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74406

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000967

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000135 Hom.: 1

Bravo AF: 0.000136

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	1.6
Dann	Benign	0.89
DEOGEN2	Benign	0.0018	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.22	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0082	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.75	N;N
REVEL	Benign	0.17
Sift	Benign	0.25	T;T
Sift4G	Benign	0.55	T;T
Polyphen		0.20	.;B
Vest4		0.059
MVP		0.040
MPC		0.064
ClinPred		0.012	T
GERP RS		-3.6
Varity_R		0.031
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs201834154; hg19: chr12-52960829;