17-40958843-G-A

Position:

• chr17-40958843-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_213656.4(KRT39):​c.1234C>T​(p.Arg412Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000459 in 1,598,314 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: KRT39 NM_213656.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.25

Genes affected

KRT39 (HGNC:32971): (keratin 39) This gene encodes a member of the type I (acidic) keratin family, which belongs to the superfamily of intermediate filament (IF) proteins. Keratins are heteropolymeric structural proteins which form the intermediate filament. These filaments, along with actin microfilaments and microtubules, compose the cytoskeleton of epithelial cells. The type I keratin genes are clustered in a region of chromosome 17q12-q21. [provided by RefSeq, Jul 2009]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014137447).
• BP6: Variant 17-40958843-G-A is Benign according to our data. Variant chr17-40958843-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2217285.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT39	NM_213656.4	c.1234C>T	p.Arg412Cys	missense_variant	7/7	ENST00000355612.7
LOC107985072	XR_001752886.2	n.81-16654G>A		intron_variant, non_coding_transcript_variant
LOC107985072	XR_001752885.2	n.81-16654G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT39	ENST00000355612.7	c.1234C>T	p.Arg412Cys	missense_variant	7/7	1	NM_213656.4	P1
KRT39	ENST00000578078.1	c.*723C>T		3_prime_UTR_variant, NMD_transcript_variant	8/8	1
	ENST00000418393.1	n.386-16654G>A		intron_variant, non_coding_transcript_variant		5
KRT39	ENST00000578029.1	n.434C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000203 AC: 49 AN: 241166 Hom.: 0 AF XY: 0.000192 AC XY: 25 AN XY: 130376

Gnomad AFR exome AF: 0.0000626

Gnomad AMR exome AF: 0.000439

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000704

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000483 AC: 698 AN: 1446170 Hom.: 0 Cov.: 31 AF XY: 0.000479 AC XY: 344 AN XY: 717650

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.000401

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.0000594

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000581

Gnomad4 OTH exome AF: 0.000352

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74316

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000324 Hom.: 1

Bravo AF: 0.000306

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000384

EpiControl AF: 0.000359

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.9
DANN	Benign	0.67
DEOGEN2	Benign	0.00042	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-2.7	N
MutationTaster	Benign	0.90	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	9.9	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.27
MVP		0.14
MPC		0.17
ClinPred		0.18	T
GERP RS		3.2
Varity_R		0.042
gMVP		0.10

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: rs142466291; hg19: chr17-39115095;