rs267606824

Variant names:

• chr14-75633653-C-T
• rs267606824
• NM_017791.3:c.977C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_017791.3(FLVCR2):​c.977C>T​(p.Ala326Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FLVCR2 NM_017791.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.58
• Publications: 3 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
• inherited retinal dystrophy

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 14-75633653-C-T is Pathogenic according to our data. Variant chr14-75633653-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1092.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLVCR2	NM_017791.3	c.977C>T	p.Ala326Val	missense_variant	Exon 4 of 10	ENST00000238667.9	NP_060261.2
FLVCR2	NM_001195283.2	c.362C>T	p.Ala121Val	missense_variant	Exon 4 of 10		NP_001182212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLVCR2	ENST00000238667.9	c.977C>T	p.Ala326Val	missense_variant	Exon 4 of 10	1	NM_017791.3	ENSP00000238667.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461712 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727184

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111852

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000653 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Fowler syndrome Pathogenic:1

Aug 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;.;T;.;.;T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;T;D;T;D;D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.;.
PhyloP100		7.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Benign	0.066	T;D;D;T;T;T;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Polyphen		0.42	B;.;.;.;.;.;.
Vest4		0.81
MutPred		0.74		Gain of catalytic residue at A321 (P = 2e-04);.;.;.;.;.;.;
MVP		0.70
MPC		0.89
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.55
gMVP		0.88
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs267606824; hg19: chr14-76099996; COSMIC: COSV99471146;