NM_004169.5:c.242+7G>A

Variant names:

• chr17-18353665-C-T
• rs2273026
• NM_004169.5:c.242+7G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004169.5(SHMT1):​c.242+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,613,322 control chromosomes in the GnomAD database, including 10,996 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (990 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10006 hom.)
• Consequence: SHMT1 NM_004169.5 splice_region, intron
• Scores: Splicing: ADA: 0.00003110
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.96
• Publications: 34 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHMT1	NM_004169.5	MANE Select	c.242+7G>A		splice_region intron	N/A	NP_004160.3
	SHMT1	NM_148918.3		c.242+7G>A		splice_region intron	N/A	NP_683718.1
	SHMT1	NM_001281786.2		c.-57+7G>A		splice_region intron	N/A	NP_001268715.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHMT1	ENST00000316694.8	TSL:1 MANE Select	c.242+7G>A		splice_region intron	N/A	ENSP00000318868.3
	SHMT1	ENST00000583780.2	TSL:1	c.242+7G>A		splice_region intron	N/A	ENSP00000462041.2
	SHMT1	ENST00000354098.7	TSL:1	c.242+7G>A		splice_region intron	N/A	ENSP00000318805.3

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16408 AN: 151988 Hom.: 992 Cov.: 32

Gnomad AFR AF: 0.0882

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.0776

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.0952

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.114

GnomAD2 exomes AF: 0.122 AC: 30730 AN: 251438 AF XY: 0.123

Gnomad AFR exome AF: 0.0901

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.0811

Gnomad EAS exome AF: 0.140

Gnomad FIN exome AF: 0.0952

Gnomad NFE exome AF: 0.0973

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.112 AC: 163481 AN: 1461216 Hom.: 10006 Cov.: 31 AF XY: 0.114 AC XY: 82916 AN XY: 726962

African (AFR) AF: 0.0894 AC: 2991 AN: 33466

American (AMR) AF: 0.187 AC: 8368 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0820 AC: 2143 AN: 26134

East Asian (EAS) AF: 0.178 AC: 7069 AN: 39694

South Asian (SAS) AF: 0.180 AC: 15530 AN: 86236

European-Finnish (FIN) AF: 0.0992 AC: 5300 AN: 53410

Middle Eastern (MID) AF: 0.0773 AC: 444 AN: 5744

European-Non Finnish (NFE) AF: 0.103 AC: 114992 AN: 1111432

Other (OTH) AF: 0.110 AC: 6644 AN: 60378

GnomAD4 genome AF: 0.108 AC: 16405 AN: 152106 Hom.: 990 Cov.: 32 AF XY: 0.111 AC XY: 8278 AN XY: 74344

African (AFR) AF: 0.0880 AC: 3652 AN: 41520

American (AMR) AF: 0.161 AC: 2450 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0776 AC: 269 AN: 3466

East Asian (EAS) AF: 0.161 AC: 833 AN: 5188

South Asian (SAS) AF: 0.182 AC: 874 AN: 4806

European-Finnish (FIN) AF: 0.0952 AC: 1006 AN: 10572

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.103 AC: 6995 AN: 67994

Other (OTH) AF: 0.113 AC: 239 AN: 2106

Alfa AF: 0.105 Hom.: 1004

Bravo AF: 0.108

Asia WGS AF: 0.148 AC: 513 AN: 3478

EpiCase AF: 0.0960

EpiControl AF: 0.0927

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.7
DANN	Benign	0.54
PhyloP100		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.060
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: rs2273026; hg19: chr17-18256979; COSMIC: COSV57399005; COSMIC: COSV57399005;