rs803455

Positions:

• chr6-150926303-A-G
• chr6-150926303-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000367321.8(MTHFD1L):​c.1256+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.933 in 1,603,946 control chromosomes in the GnomAD database, including 699,004 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 0.94 (67602 hom., cov: 32)
  • Exomes 𝑓: 0.93 (631402 hom.)
• Consequence: MTHFD1L ENST00000367321.8 splice_region, intron
• Scores: Splicing: ADA: 0.00002141
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.312

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFD1L	NM_015440.5	c.1256+8A>G		splice_region_variant, intron_variant		ENST00000367321.8	NP_056255.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFD1L	ENST00000367321.8	c.1256+8A>G		splice_region_variant, intron_variant		1	NM_015440.5	ENSP00000356290	P4
MTHFD1L	ENST00000611279.4	c.1259+8A>G		splice_region_variant, intron_variant		5		ENSP00000478253	A1
MTHFD1L	ENST00000618312.4	c.1061+8A>G		splice_region_variant, intron_variant		5		ENSP00000479539
MTHFD1L	ENST00000441122.5	c.*462+8A>G		splice_region_variant, intron_variant, NMD_transcript_variant		5		ENSP00000407070

Frequencies

GnomAD3 genomes AF: 0.942 AC: 143318 AN: 152142 Hom.: 67549 Cov.: 32

Gnomad AFR AF: 0.979

Gnomad AMI AF: 0.969

Gnomad AMR AF: 0.875

Gnomad ASJ AF: 0.928

Gnomad EAS AF: 0.899

Gnomad SAS AF: 0.956

Gnomad FIN AF: 0.951

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.936

Gnomad OTH AF: 0.925

GnomAD3 exomes AF: 0.924 AC: 230206 AN: 249206 Hom.: 106531 AF XY: 0.927 AC XY: 124862 AN XY: 134728

Gnomad AFR exome AF: 0.982

Gnomad AMR exome AF: 0.835

Gnomad ASJ exome AF: 0.928

Gnomad EAS exome AF: 0.893

Gnomad SAS exome AF: 0.957

Gnomad FIN exome AF: 0.949

Gnomad NFE exome AF: 0.933

Gnomad OTH exome AF: 0.921

GnomAD4 exome AF: 0.932 AC: 1353475 AN: 1451686 Hom.: 631402 Cov.: 34 AF XY: 0.933 AC XY: 672567 AN XY: 720932

Gnomad4 AFR exome AF: 0.983

Gnomad4 AMR exome AF: 0.833

Gnomad4 ASJ exome AF: 0.928

Gnomad4 EAS exome AF: 0.920

Gnomad4 SAS exome AF: 0.956

Gnomad4 FIN exome AF: 0.948

Gnomad4 NFE exome AF: 0.933

Gnomad4 OTH exome AF: 0.927

GnomAD4 genome AF: 0.942 AC: 143428 AN: 152260 Hom.: 67602 Cov.: 32 AF XY: 0.943 AC XY: 70163 AN XY: 74436

Gnomad4 AFR AF: 0.979

Gnomad4 AMR AF: 0.875

Gnomad4 ASJ AF: 0.928

Gnomad4 EAS AF: 0.899

Gnomad4 SAS AF: 0.957

Gnomad4 FIN AF: 0.951

Gnomad4 NFE AF: 0.936

Gnomad4 OTH AF: 0.925

Alfa AF: 0.935 Hom.: 97008

Bravo AF: 0.937

Asia WGS AF: 0.915 AC: 3184 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.30
DANN	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs803455; hg19: chr6-151247439;