chr6-150926303-A-G

Variant names:

• chr6-150926303-A-G
• rs803455
• NM_015440.5:c.1256+8A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001242767.2(MTHFD1L):​c.1259+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 NM_001242767.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002141
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.312
• Publications: 11 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242767.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1L	NM_015440.5	MANE Select	c.1256+8A>G		splice_region intron	N/A	NP_056255.2
	MTHFD1L	NM_001242767.2		c.1259+8A>G		splice_region intron	N/A	NP_001229696.1
	MTHFD1L	NM_001242768.2		c.1061+8A>G		splice_region intron	N/A	NP_001229697.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1L	ENST00000367321.8	TSL:1 MANE Select	c.1256+8A>G		splice_region intron	N/A	ENSP00000356290.3
	MTHFD1L	ENST00000611279.4	TSL:5	c.1259+8A>G		splice_region intron	N/A	ENSP00000478253.1
	MTHFD1L	ENST00000939695.1		c.1250+8A>G		splice_region intron	N/A	ENSP00000609754.1

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

GnomAD2 exomes AF: 0.924 AC: 230206 AN: 249206 AF XY: 0.927

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 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

African (AFR) AF: 0.983 AC: 32738 AN: 33290

American (AMR) AF: 0.833 AC: 36874 AN: 44254

Ashkenazi Jewish (ASJ) AF: 0.928 AC: 24085 AN: 25946

East Asian (EAS) AF: 0.920 AC: 36278 AN: 39454

South Asian (SAS) AF: 0.956 AC: 81776 AN: 85564

European-Finnish (FIN) AF: 0.948 AC: 50296 AN: 53074

Middle Eastern (MID) AF: 0.907 AC: 5193 AN: 5724

European-Non Finnish (NFE) AF: 0.933 AC: 1030620 AN: 1104396

Other (OTH) AF: 0.927 AC: 55615 AN: 59984

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

African (AFR) AF: 0.979 AC: 40686 AN: 41560

American (AMR) AF: 0.875 AC: 13377 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.928 AC: 3223 AN: 3472

East Asian (EAS) AF: 0.899 AC: 4646 AN: 5166

South Asian (SAS) AF: 0.957 AC: 4617 AN: 4826

European-Finnish (FIN) AF: 0.951 AC: 10089 AN: 10612

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.936 AC: 63696 AN: 68018

Other (OTH) AF: 0.925 AC: 1951 AN: 2110

Alfa AF: 0.936 Hom.: 206389

Bravo AF: 0.937

Asia WGS AF: 0.915 AC: 3184 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	0.30
DANN	Benign	0.43
PhyloP100		-0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs803455; hg19: chr6-151247439;