1-36341963-G-A

Variant names:

• chr1-36341963-G-A
• rs202225847
• NM_001282547.2:c.1100C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001282547.2(STK40):​c.1100C>T​(p.Thr367Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,613,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T367T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: STK40 NM_001282547.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.43
• Publications: 3 publications found

Genes affected

STK40 (HGNC:21373): (serine/threonine kinase 40) Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Predicted to be involved in protein phosphorylation. Predicted to act upstream of or within several processes, including glycogen metabolic process; lung development; and respiratory system process. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04559809).
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK40	NM_001282547.2	c.1100C>T	p.Thr367Met	missense_variant	Exon 11 of 11	ENST00000373132.4	NP_001269476.1
STK40	NM_001282546.2	c.1115C>T	p.Thr372Met	missense_variant	Exon 11 of 11		NP_001269475.1
STK40	NM_032017.3	c.1100C>T	p.Thr367Met	missense_variant	Exon 12 of 12		NP_114406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK40	ENST00000373132.4	c.1100C>T	p.Thr367Met	missense_variant	Exon 11 of 11	1	NM_001282547.2	ENSP00000362224.4
STK40	ENST00000373130.7	c.1115C>T	p.Thr372Met	missense_variant	Exon 11 of 11	1		ENSP00000362222.3
STK40	ENST00000373129.7	c.1100C>T	p.Thr367Met	missense_variant	Exon 12 of 12	1		ENSP00000362221.3
STK40	ENST00000359297.6	c.*1236C>T		3_prime_UTR_variant	Exon 9 of 9	2		ENSP00000352245.2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152256 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000147 AC: 36 AN: 245500 AF XY: 0.000120

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.000789

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000219

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000274

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000561 AC: 82 AN: 1460674 Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38 AN XY: 726590

African (AFR) AF: 0.0000299 AC: 1 AN: 33460

American (AMR) AF: 0.000561 AC: 25 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1111412

Other (OTH) AF: 0.0000497 AC: 3 AN: 60316

GnomAD4 genome AF: 0.0000656 AC: 10 AN: 152374 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74512

African (AFR) AF: 0.0000481 AC: 2 AN: 41594

American (AMR) AF: 0.000196 AC: 3 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1100C>T (p.T367M) alteration is located in exon 12 (coding exon 10) of the STK40 gene. This alteration results from a C to T substitution at nucleotide position 1100, causing the threonine (T) at amino acid position 367 to be replaced by a methionine (M). 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	0.073
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	T;.;T
Eigen	Benign	-0.080
Eigen_PC	Benign	-0.054
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.046	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.69	N;.;N
PhyloP100		7.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.012	D;D;D
Sift4G	Benign	0.062	T;T;T
Polyphen		0.66	P;P;P
Vest4		0.33
MVP		0.48
MPC		0.43
ClinPred		0.071	T
GERP RS		3.1
Varity_R		0.040
gMVP		0.21
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs202225847; hg19: chr1-36807564;