chr11-72192471-G-A

Variant names:

• chr11-72192471-G-A
• rs7938669
• NM_016729.3:c.168+130G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016729.3(FOLR1):​c.168+130G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000132 in 757,014 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000013 (0 hom.)
• Consequence: FOLR1 NM_016729.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.403
• Publications: 1 publications found

Genes affected

FOLR1 (HGNC:3791): (folate receptor alpha) The protein encoded by this gene is a member of the folate receptor family. Members of this gene family bind folic acid and its reduced derivatives, and transport 5-methyltetrahydrofolate into cells. This gene product is a secreted protein that either anchors to membranes via a glycosyl-phosphatidylinositol linkage or exists in a soluble form. Mutations in this gene have been associated with neurodegeneration due to cerebral folate transport deficiency. Due to the presence of two promoters, multiple transcription start sites, and alternative splicing, multiple transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2009]

FOLR1 Gene-Disease associations (from GenCC):

• neurodegenerative syndrome due to cerebral folate transport deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ENSG00000204971 (HGNC:58347):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016729.3. 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
	FOLR1	NM_016729.3	MANE Select	c.168+130G>A		intron	N/A	NP_057941.1
	FOLR1	NM_000802.3		c.168+130G>A		intron	N/A	NP_000793.1
	FOLR1	NM_016724.3		c.168+130G>A		intron	N/A	NP_057936.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOLR1	ENST00000393676.5	TSL:1 MANE Select	c.168+130G>A		intron	N/A	ENSP00000377281.3
	FOLR1	ENST00000312293.9	TSL:1	c.168+130G>A		intron	N/A	ENSP00000308137.4
	FOLR1	ENST00000393679.5	TSL:1	c.168+130G>A		intron	N/A	ENSP00000377284.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000132 AC: 1 AN: 757014 Hom.: 0 AF XY: 0.00000255 AC XY: 1 AN XY: 391786

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 19640

American (AMR) AF: 0.00 AC: 0 AN: 32478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18096

East Asian (EAS) AF: 0.00 AC: 0 AN: 34756

South Asian (SAS) AF: 0.00 AC: 0 AN: 61026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2666

European-Non Finnish (NFE) AF: 0.00000196 AC: 1 AN: 509832

Other (OTH) AF: 0.00 AC: 0 AN: 36662

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.38
DANN	Benign	0.56
PhyloP100		-0.40
PromoterAI		0.00030	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs7938669; hg19: chr11-71903515;