17-41422326-C-G

Variant names:

• chr17-41422326-C-G
• NM_003770.5:c.841G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003770.5(KRT37):​c.841G>C​(p.Glu281Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E281K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRT37 NM_003770.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.97

Genes affected

KRT37 (HGNC:6455): (keratin 37) 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]

ENSG00000234859 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT37	NM_003770.5	c.841G>C	p.Glu281Gln	missense_variant	Exon 4 of 7	ENST00000225550.4	NP_003761.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT37	ENST00000225550.4	c.841G>C	p.Glu281Gln	missense_variant	Exon 4 of 7	1	NM_003770.5	ENSP00000225550.3
ENSG00000234859	ENST00000432258.1	n.2195-1028C>G		intron_variant	Intron 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 33 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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.87		Loss of disorder (P = 0.1788);
MVP		0.91
MPC		0.37
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.66
gMVP		0.13

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: chr17-39578578;