Genetic Variant MTHFD1L:c.781-6541A>G (chr6-150899109-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_015440.5(MTHFD1L):c.781-6541A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.534 in 448,792 control chromosomes in the GnomAD database, including 65,886 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.56 ( 24021 hom., cov: 32)

Exomes 𝑓: 0.52 ( 41865 hom. )

Consequence

MTHFD1L
NM_015440.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.318

Publications

3 publications found

Variant links:

Genes affected

MTHFD1L (HGNC:21055): (methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 like) The protein encoded by this gene is involved in the synthesis of tetrahydrofolate (THF) in the mitochondrion. THF is important in the de novo synthesis of purines and thymidylate and in the regeneration of methionine from homocysteine. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jun 2011]

MTHFD1L links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.796 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015440.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MTHFD1L	NM_015440.5	MANE Select	c.781-6541A>G	intron	N/A	NP_056255.2
MTHFD1L	NM_001242767.2		c.784-6541A>G	intron	N/A	NP_001229696.1	B7ZM99
MTHFD1L	NM_001242768.2		c.586-6541A>G	intron	N/A	NP_001229697.1	A0A087WVM4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MTHFD1L	ENST00000367321.8	TSL:1 MANE Select	c.781-6541A>G	intron	N/A	ENSP00000356290.3	Q6UB35-1
MTHFD1L	ENST00000611279.4	TSL:5	c.784-6541A>G	intron	N/A	ENSP00000478253.1	B7ZM99
MTHFD1L	ENST00000939695.1		c.775-6541A>G	intron	N/A	ENSP00000609754.1

Frequencies

GnomAD3 genomes

AF:

0.556

AC:

84457

AN:

151918

Hom.:

23996

Cov.:

show subpopulations

Gnomad AFR

AF:

0.523

Gnomad AMI

AF:

0.521

Gnomad AMR

AF:

0.652

Gnomad ASJ

AF:

0.512

Gnomad EAS

AF:

0.816

Gnomad SAS

AF:

0.727

Gnomad FIN

AF:

0.622

Gnomad MID

AF:

0.389

Gnomad NFE

AF:

0.515

Gnomad OTH

AF:

0.561

GnomAD4 exome

AF:

0.522

AC:

154911

AN:

296756

Hom.:

41865

AF XY:

0.522

AC XY:

73999

AN XY:

141764

show subpopulations

African (AFR)

AF:

0.522

AC:

2762

AN:

5288

American (AMR)

AF:

0.631

AC:

328

AN:

520

Ashkenazi Jewish (ASJ)

AF:

0.490

AC:

894

AN:

1826

East Asian (EAS)

AF:

0.802

AC:

1065

AN:

1328

South Asian (SAS)

AF:

0.708

AC:

4188

AN:

5916

European-Finnish (FIN)

AF:

0.563

AC:

AN:

160

Middle Eastern (MID)

AF:

0.400

AC:

800

AN:

2000

European-Non Finnish (NFE)

AF:

0.517

AC:

139451

AN:

269850

Other (OTH)

AF:

0.540

AC:

5333

AN:

9868

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

3583

7166

10750

14333

17916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5436

10872

16308

21744

27180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.556

AC:

84528

AN:

152036

Hom.:

24021

Cov.:

AF XY:

0.567

AC XY:

42158

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.523

AC:

21692

AN:

41468

American (AMR)

AF:

0.653

AC:

9973

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.512

AC:

1775

AN:

3468

East Asian (EAS)

AF:

0.816

AC:

4231

AN:

5182

South Asian (SAS)

AF:

0.726

AC:

3504

AN:

4826

European-Finnish (FIN)

AF:

0.622

AC:

6567

AN:

10552

Middle Eastern (MID)

AF:

0.387

AC:

113

AN:

292

European-Non Finnish (NFE)

AF:

0.515

AC:

35015

AN:

67958

Other (OTH)

AF:

0.562

AC:

1183

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1890

3781

5671

7562

9452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

732

1464

2196

2928

3660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.534

Hom.:

2768

Bravo

AF:

0.553

Asia WGS

AF:

0.728

AC:

2534

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.58

(source)

DANN

Benign

0.80

PhyloP100

-0.32

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over