chr14-75634779-C-T

Variant names:

• chr14-75634779-C-T
• rs45592848
• NM_017791.3:c.1021-131C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_017791.3(FLVCR2):​c.1021-131C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00806 in 679,272 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (30 hom.)
• Consequence: FLVCR2 NM_017791.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.362
• Publications: 0 publications found

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]

TTLL5 (HGNC:19963): (tubulin tyrosine ligase like 5) This gene encodes a member of the tubulin tyrosine ligase like protein family. This protein interacts with two glucocorticoid receptor coactivators, transcriptional intermediary factor 2 and steroid receptor coactivator 1. This protein may function as a coregulator of glucocorticoid receptor mediated gene induction and repression. This protein may also function as an alpha tubulin polyglutamylase.[provided by RefSeq, Feb 2010]

TTLL5 Gene-Disease associations (from GenCC):

• cone-rod dystrophy 19

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• TTLL5-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 14-75634779-C-T is Benign according to our data. Variant chr14-75634779-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1312711.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00724 (1103/152276) while in subpopulation NFE AF = 0.00913 (621/68024). AF 95% confidence interval is 0.00853. There are 10 homozygotes in GnomAd4. There are 592 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017791.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLVCR2	NM_017791.3	MANE Select	c.1021-131C>T		intron	N/A	NP_060261.2	Q9UPI3-1
	FLVCR2	NM_001195283.2		c.406-131C>T		intron	N/A	NP_001182212.1	Q9UPI3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLVCR2	ENST00000238667.9	TSL:1 MANE Select	c.1021-131C>T		intron	N/A	ENSP00000238667.4	Q9UPI3-1
	FLVCR2	ENST00000852195.1		c.1075-131C>T		intron	N/A	ENSP00000522253.1
	FLVCR2	ENST00000852190.1		c.991-131C>T		intron	N/A	ENSP00000522250.1

Frequencies

GnomAD3 genomes AF: 0.00726 AC: 1105 AN: 152158 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0333

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00913

Gnomad OTH AF: 0.00334

GnomAD4 exome AF: 0.00830 AC: 4374 AN: 526996 Hom.: 30 AF XY: 0.00783 AC XY: 2202 AN XY: 281132

African (AFR) AF: 0.00155 AC: 23 AN: 14824

American (AMR) AF: 0.00324 AC: 102 AN: 31448

Ashkenazi Jewish (ASJ) AF: 0.00221 AC: 40 AN: 18086

East Asian (EAS) AF: 0.00 AC: 0 AN: 31536

South Asian (SAS) AF: 0.000210 AC: 12 AN: 57076

European-Finnish (FIN) AF: 0.0260 AC: 1052 AN: 40420

Middle Eastern (MID) AF: 0.00210 AC: 5 AN: 2384

European-Non Finnish (NFE) AF: 0.00970 AC: 2932 AN: 302298

Other (OTH) AF: 0.00719 AC: 208 AN: 28924

GnomAD4 genome AF: 0.00724 AC: 1103 AN: 152276 Hom.: 10 Cov.: 32 AF XY: 0.00795 AC XY: 592 AN XY: 74458

African (AFR) AF: 0.00152 AC: 63 AN: 41552

American (AMR) AF: 0.00261 AC: 40 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0333 AC: 353 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00913 AC: 621 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.0119 Hom.: 2

Bravo AF: 0.00467

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.7
DANN	Benign	0.62
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs45592848; hg19: chr14-76101122;