17-41420919-C-G

Variant names:

• chr17-41420919-C-G
• rs150463302
• NM_003770.5:c.1309G>C

Variant summary

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

The NM_003770.5(KRT37):​c.1309G>C​(p.Gly437Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,613,988 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: KRT37 NM_003770.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.353

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0051659048).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT37	NM_003770.5	c.1309G>C	p.Gly437Arg	missense_variant	Exon 7 of 7	ENST00000225550.4	NP_003761.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT37	ENST00000225550.4	c.1309G>C	p.Gly437Arg	missense_variant	Exon 7 of 7	1	NM_003770.5	ENSP00000225550.3
ENSG00000234859	ENST00000432258.1	n.2195-2435C>G		intron_variant	Intron 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000382 AC: 96 AN: 251218 Hom.: 1 AF XY: 0.000442 AC XY: 60 AN XY: 135778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000211 AC: 308 AN: 1461704 Hom.: 1 Cov.: 30 AF XY: 0.000254 AC XY: 185 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00406

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000908

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74450

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000812 Hom.: 0

Bravo AF: 0.000268

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000288 AC: 35

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1309G>C (p.G437R) alteration is located in exon 7 (coding exon 7) of the KRT37 gene. This alteration results from a G to C substitution at nucleotide position 1309, causing the glycine (G) at amino acid position 437 to be replaced by an arginine (R). 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	0.15
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	0.60
DANN	Benign	0.59
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.016	N
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.34	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.18
Sift	Benign	0.26	T
Sift4G	Benign	0.57	T
Polyphen		0.37	B
Vest4		0.26
MVP		0.42
MPC		0.068
ClinPred		0.033	T
GERP RS		3.3
Varity_R		0.027
gMVP		0.059

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: rs150463302; hg19: chr17-39577171;