17-40960371-T-C

Position:

• chr17-40960371-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_213656.4(KRT39):​c.1127A>G​(p.Asn376Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT39 NM_213656.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.989

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3006493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT39	NM_213656.4	c.1127A>G	p.Asn376Ser	missense_variant	6/7	ENST00000355612.7
LOC107985072	XR_001752886.2	n.81-15126T>C		intron_variant, non_coding_transcript_variant
LOC107985072	XR_001752885.2	n.81-15126T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT39	ENST00000355612.7	c.1127A>G	p.Asn376Ser	missense_variant	6/7	1	NM_213656.4	P1
KRT39	ENST00000578078.1	c.*616A>G		3_prime_UTR_variant, NMD_transcript_variant	7/8	1
	ENST00000418393.1	n.386-15126T>C		intron_variant, non_coding_transcript_variant		5
KRT39	ENST00000578029.1	n.327A>G		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Sep 17, 2021

The c.1127A>G (p.N376S) alteration is located in exon 6 (coding exon 6) of the KRT39 gene. This alteration results from a A to G substitution at nucleotide position 1127, causing the asparagine (N) at amino acid position 376 to be replaced by a serine (S). 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	0.16
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Benign	0.082
Eigen_PC	Benign	0.022
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	-0.053	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.26
Sift	Benign	0.043	D
Sift4G	Benign	0.072	T
Polyphen		0.96	D
Vest4		0.10
MutPred		0.41		Gain of phosphorylation at N376 (P = 0.0343);
MVP		0.58
MPC		0.18
ClinPred		0.95	D
GERP RS		4.6
Varity_R		0.26
gMVP		0.22

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: chr17-39116623;