17-41438201-G-T

Position:

• chr17-41438201-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000246646.4(KRT38):​c.1133C>A​(p.Ala378Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KRT38 ENST00000246646.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.638

Genes affected

KRT38 (HGNC:6456): (keratin 38) The protein encoded by this gene is a member of the keratin gene family. As a type I hair keratin, it is an acidic protein which heterodimerizes with type II keratins to form hair and nails. The type I hair keratins are clustered in a region of chromosome 17q12-q21 and have the same direction of transcription. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT38	NM_006771.4	c.1133C>A	p.Ala378Asp	missense_variant	6/7	ENST00000246646.4	NP_006762.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT38	ENST00000246646.4	c.1133C>A	p.Ala378Asp	missense_variant	6/7	1	NM_006771.4	ENSP00000246646.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

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

May 23, 2024

The c.1133C>A (p.A378D) alteration is located in exon 6 (coding exon 6) of the KRT38 gene. This alteration results from a C to A substitution at nucleotide position 1133, causing the alanine (A) at amino acid position 378 to be replaced by an aspartic acid (D). 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	Uncertain	0.36
BayesDel_addAF	Benign	0.0044	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.46
MutPred		0.54		Gain of disorder (P = 0.1021);
MVP		0.79
MPC		0.31
ClinPred		0.98	D
GERP RS		-2.5
Varity_R		0.77
gMVP		0.23

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: rs750162789; hg19: chr17-39594453;