NM_001159377.2:c.1097G>A

Variant names:

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

Variant summary

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

The NM_001159377.2(MTHFSD):​c.1097G>A​(p.Arg366His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,521,470 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. 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. R366C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: MTHFSD NM_001159377.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B: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: 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=0.15933526).

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>A	p.Arg366His	missense	Exon 8 of 8	NP_001152849.1	Q2M296-1
	MTHFSD	NM_001159378.2		c.1097G>A	p.Arg366His	missense	Exon 8 of 8	NP_001152850.1	Q2M296-3
	MTHFSD	NM_001159379.2		c.1094G>A	p.Arg365His	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>A	p.Arg366His	missense	Exon 8 of 8	ENSP00000354152.6	Q2M296-1
	MTHFSD	ENST00000381214.9	TSL:1	c.1097G>A	p.Arg366His	missense	Exon 8 of 8	ENSP00000370612.5	Q2M296-3
	MTHFSD	ENST00000543303.6	TSL:1	c.1094G>A	p.Arg365His	missense	Exon 8 of 8	ENSP00000444003.2	Q2M296-4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151696 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00000597 AC: 1 AN: 167510 AF XY: 0.0000108

Gnomad AFR exome AF: 0.00

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: 0.0000161 AC: 22 AN: 1369774 Hom.: 0 Cov.: 29 AF XY: 0.0000179 AC XY: 12 AN XY: 671834

African (AFR) AF: 0.00 AC: 0 AN: 30618

American (AMR) AF: 0.0000297 AC: 1 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: 0.0000268 AC: 2 AN: 74626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42928

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

European-Non Finnish (NFE) AF: 0.0000169 AC: 18 AN: 1067860

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

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151696 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74050

African (AFR) AF: 0.0000484 AC: 2 AN: 41336

American (AMR) AF: 0.00 AC: 0 AN: 15260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5060

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67902

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000170 AC: 2

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.064
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.9
DANN	Benign	0.94
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.74	N
PhyloP100		-0.67
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.015
Sift	Benign	0.15	T
Sift4G	Benign	0.28	T
Polyphen		0.021	B
Vest4		0.087
MutPred		0.41		Loss of MoRF binding (P = 0.0053)
MVP		0.076
MPC		0.021
ClinPred		0.16	T
GERP RS		-3.9
Varity_R		0.045
gMVP		0.20
Mutation Taster		=95/5	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: COSV59804603; COSMIC: COSV59804603;