Genetic Variant NM_015440.5:c.228-74C>G (chr6-150876016-C-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.228-74C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 1,201,496 control chromosomes in the GnomAD database, including 76,078 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 0.34 ( 9162 hom., cov: 32)

Exomes 𝑓: 0.35 ( 66916 hom. )

Consequence

MTHFD1L
NM_015440.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.116

Publications

9 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:

Genome browser will be placed here

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=-0.92).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFD1L	NM_015440.5 link	c.228-74C>G		intron_variant	Intron 1 of 27	ENST00000367321.8	NP_056255.2	Q6UB35-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFD1L	ENST00000367321.8 link	c.228-74C>G		intron_variant	Intron 1 of 27	1	NM_015440.5	ENSP00000356290.3		Q6UB35-1

Frequencies

GnomAD3 genomes

AF:

0.344

AC:

52258

AN:

151920

Hom.:

9155

Cov.:

show subpopulations

Gnomad AFR

AF:

0.335

Gnomad AMI

AF:

0.399

Gnomad AMR

AF:

0.277

Gnomad ASJ

AF:

0.362

Gnomad EAS

AF:

0.223

Gnomad SAS

AF:

0.341

Gnomad FIN

AF:

0.369

Gnomad MID

AF:

0.373

Gnomad NFE

AF:

0.368

Gnomad OTH

AF:

0.365

GnomAD2 exomes

AF:

0.323

AC:

58451

AN:

181142

AF XY:

0.330

show subpopulations

Gnomad AFR exome

AF:

0.333

Gnomad AMR exome

AF:

0.195

Gnomad ASJ exome

AF:

0.348

Gnomad EAS exome

AF:

0.233

Gnomad FIN exome

AF:

0.366

Gnomad NFE exome

AF:

0.361

Gnomad OTH exome

AF:

0.346

GnomAD4 exome

AF:

0.353

AC:

370420

AN:

1049458

Hom.:

66916

Cov.:

AF XY:

0.353

AC XY:

188749

AN XY:

535216

show subpopulations

African (AFR)

AF:

0.339

AC:

8353

AN:

24636

American (AMR)

AF:

0.208

AC:

7301

AN:

35034

Ashkenazi Jewish (ASJ)

AF:

0.354

AC:

8118

AN:

22938

East Asian (EAS)

AF:

0.237

AC:

8687

AN:

36702

South Asian (SAS)

AF:

0.329

AC:

23406

AN:

71174

European-Finnish (FIN)

AF:

0.369

AC:

18802

AN:

50904

Middle Eastern (MID)

AF:

0.373

AC:

1824

AN:

4892

European-Non Finnish (NFE)

AF:

0.366

AC:

277259

AN:

756916

Other (OTH)

AF:

0.360

AC:

16670

AN:

46262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

11124

22248

33373

44497

55621

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7512

15024

22536

30048

37560

<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:

0.344

AC:

52300

AN:

152038

Hom.:

9162

Cov.:

AF XY:

0.341

AC XY:

25357

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.335

AC:

13910

AN:

41484

American (AMR)

AF:

0.276

AC:

4217

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.362

AC:

1254

AN:

3468

East Asian (EAS)

AF:

0.223

AC:

1154

AN:

5174

South Asian (SAS)

AF:

0.341

AC:

1646

AN:

4822

European-Finnish (FIN)

AF:

0.369

AC:

3899

AN:

10556

Middle Eastern (MID)

AF:

0.361

AC:

106

AN:

294

European-Non Finnish (NFE)

AF:

0.367

AC:

24975

AN:

67960

Other (OTH)

AF:

0.367

AC:

776

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1772

3544

5315

7087

8859

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

520

1040

1560

2080

2600

<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:

0.351

Hom.:

1749

Bravo

AF:

0.334

Asia WGS

AF:

0.315

AC:

1097

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.91

(source)

DANN

Benign

0.35

PhyloP100

-0.12

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over