14-75578862-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017791.3(FLVCR2):c.-111T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00591 in 1,006,838 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (27 hom.)
• Consequence: FLVCR2 NM_017791.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0490

Genes affected

FLVCR2 (HGNC:20105): (FLVCR choline and putative heme transporter 2) This gene encodes a member of the major facilitator superfamily. The encoded transmembrane protein is a calcium transporter. Unlike the related protein feline leukemia virus subgroup C receptor 1, the protein encoded by this locus does not bind to feline leukemia virus subgroup C envelope protein. The encoded protein may play a role in development of brain vascular endothelial cells, as mutations at this locus have been associated with proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome. Alternatively spliced transcript variants have been described.[provided by RefSeq, Aug 2010]

FLVCR2-AS1 (HGNC:55854): (FLVCR2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 14-75578862-T-C is Benign according to our data. Variant chr14-75578862-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 314405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00929 (1415/152296) while in subpopulation AFR AF= 0.0193 (803/41556). AF 95% confidence interval is 0.0182. There are 8 homozygotes in gnomad4. There are 675 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLVCR2	NM_017791.3	c.-111T>C		5_prime_UTR_variant	1/10	ENST00000238667.9
FLVCR2-AS1	NR_110552.1	n.727A>G		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLVCR2	ENST00000238667.9	c.-111T>C		5_prime_UTR_variant	1/10	1	NM_017791.3	P1
FLVCR2-AS1	ENST00000455232.1	n.727A>G		non_coding_transcript_exon_variant	1/3	1
FLVCR2-AS1	ENST00000693551.1	n.791A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00929 AC: 1413 AN: 152178 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00522

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.00531 AC: 4534 AN: 854542 Hom.: 27 Cov.: 11 AF XY: 0.00525 AC XY: 2336 AN XY: 445142

Gnomad4 AFR exome AF: 0.0194

Gnomad4 AMR exome AF: 0.00553

Gnomad4 ASJ exome AF: 0.0207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.000873

Gnomad4 NFE exome AF: 0.00509

Gnomad4 OTH exome AF: 0.00714

GnomAD4 genome AF: 0.00929 AC: 1415 AN: 152296 Hom.: 8 Cov.: 32 AF XY: 0.00906 AC XY: 675 AN XY: 74482

Gnomad4 AFR AF: 0.0193

Gnomad4 AMR AF: 0.00928

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00522

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00656 Hom.: 0

Bravo AF: 0.0103

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Posterior column ataxia-retinitis pigmentosa syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 13, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	7.4
Dann	Benign	0.70

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

LitVar

Other links and lift over

dbSNP: rs80001297; hg19: chr14-76045205;