17-18340051-T-A

Variant names:

• chr17-18340051-T-A
• rs768374149
• NM_004169.5:c.806A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004169.5(SHMT1):​c.806A>T​(p.Tyr269Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. Y269C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SHMT1 NM_004169.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.90
• Publications: 0 publications found

Genes affected

SHMT1 (HGNC:10850): (serine hydroxymethyltransferase 1) This gene encodes the cytosolic form of serine hydroxymethyltransferase, a pyridoxal phosphate-containing enzyme that catalyzes the reversible conversion of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate. This reaction provides one-carbon units for synthesis of methionine, thymidylate, and purines in the cytoplasm. This gene is located within the Smith-Magenis syndrome region on chromosome 17. A pseudogene of this gene is located on the short arm of chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20263076).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004169.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHMT1	NM_004169.5	MANE Select	c.806A>T	p.Tyr269Phe	missense	Exon 7 of 12	NP_004160.3
	SHMT1	NM_148918.3		c.806A>T	p.Tyr269Phe	missense	Exon 7 of 11	NP_683718.1	P34896-2
	SHMT1	NM_001281786.2		c.392A>T	p.Tyr131Phe	missense	Exon 6 of 11	NP_001268715.1	P34896-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHMT1	ENST00000316694.8	TSL:1 MANE Select	c.806A>T	p.Tyr269Phe	missense	Exon 7 of 12	ENSP00000318868.3	P34896-1
	SHMT1	ENST00000583780.2	TSL:1	c.806A>T	p.Tyr269Phe	missense	Exon 8 of 13	ENSP00000462041.2	P34896-1
	SHMT1	ENST00000354098.7	TSL:1	c.806A>T	p.Tyr269Phe	missense	Exon 7 of 11	ENSP00000318805.3	P34896-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461266 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726968

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Benign	0.50
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.98	L
PhyloP100		2.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.074
Sift	Benign	0.90	T
Sift4G	Benign	1.0	T
Polyphen		0.019	B
Vest4		0.36
MutPred		0.48		Loss of methylation at K274 (P = 0.1032)
MVP		0.34
MPC		0.20
ClinPred		0.55	D
GERP RS		4.5
Varity_R		0.25
gMVP		0.62
Mutation Taster		=49/51	disease causing

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: rs768374149; hg19: chr17-18243365;