NM_001159377.2:c.1097G>T

Variant names:

• chr16-86532066-C-A
• rs372334535
• NM_001159377.2:c.1097G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001159377.2(MTHFSD):​c.1097G>T​(p.Arg366Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 1,521,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R366C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: MTHFSD NM_001159377.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.670
• Publications: 3 publications found

Genes affected

MTHFSD (HGNC:25778): (methenyltetrahydrofolate synthetase domain containing) Enables RNA binding activity. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09620175).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159377.2. 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
	MTHFSD	NM_001159377.2	MANE Select	c.1097G>T	p.Arg366Leu	missense	Exon 8 of 8	NP_001152849.1	Q2M296-1
	MTHFSD	NM_001159378.2		c.1097G>T	p.Arg366Leu	missense	Exon 8 of 8	NP_001152850.1	Q2M296-3
	MTHFSD	NM_001159379.2		c.1094G>T	p.Arg365Leu	missense	Exon 8 of 8	NP_001152851.1	Q2M296-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFSD	ENST00000360900.11	TSL:1 MANE Select	c.1097G>T	p.Arg366Leu	missense	Exon 8 of 8	ENSP00000354152.6	Q2M296-1
	MTHFSD	ENST00000381214.9	TSL:1	c.1097G>T	p.Arg366Leu	missense	Exon 8 of 8	ENSP00000370612.5	Q2M296-3
	MTHFSD	ENST00000543303.6	TSL:1	c.1094G>T	p.Arg365Leu	missense	Exon 8 of 8	ENSP00000444003.2	Q2M296-4

Frequencies

GnomAD3 genomes AF: 0.000185 AC: 28 AN: 151696 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000298 AC: 5 AN: 167510 AF XY: 0.0000324

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000183 AC: 25 AN: 1369768 Hom.: 0 Cov.: 29 AF XY: 0.0000119 AC XY: 8 AN XY: 671830

African (AFR) AF: 0.000784 AC: 24 AN: 30618

American (AMR) AF: 0.00 AC: 0 AN: 33632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21692

East Asian (EAS) AF: 0.00 AC: 0 AN: 37430

South Asian (SAS) AF: 0.00 AC: 0 AN: 74626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4626

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1067856

Other (OTH) AF: 0.0000177 AC: 1 AN: 56362

GnomAD4 genome AF: 0.000184 AC: 28 AN: 151814 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74178

African (AFR) AF: 0.000651 AC: 27 AN: 41458

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5048

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67894

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000219

ESP6500AA AF: 0.000561 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000510 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Benign	0.0013	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.67
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.052
Sift	Benign	0.10	T
Sift4G	Benign	0.38	T
Polyphen		0.60	P
Vest4		0.27
MVP		0.18
MPC		0.030
ClinPred		0.061	T
GERP RS		-3.9
Varity_R		0.18
gMVP		0.34
Mutation Taster		=91/9	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: rs372334535; hg19: chr16-86565672; COSMIC: COSV59804967; COSMIC: COSV59804967;