14-75633674-G-C

Variant names:

• chr14-75633674-G-C
• rs757778790
• NM_017791.3:c.998G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_017791.3(FLVCR2):​c.998G>C​(p.Arg333Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R333H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLVCR2 NM_017791.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.52
• Publications: 4 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_017791.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-75633674-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191048.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLVCR2	NM_017791.3	MANE Select	c.998G>C	p.Arg333Pro	missense	Exon 4 of 10	NP_060261.2
	FLVCR2	NM_001195283.2		c.383G>C	p.Arg128Pro	missense	Exon 4 of 10	NP_001182212.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLVCR2	ENST00000238667.9	TSL:1 MANE Select	c.998G>C	p.Arg333Pro	missense	Exon 4 of 10	ENSP00000238667.4
	FLVCR2	ENST00000539311.5	TSL:2	c.383G>C	p.Arg128Pro	missense	Exon 4 of 10	ENSP00000443439.1
	FLVCR2	ENST00000555027.1	TSL:3	c.143G>C	p.Arg48Pro	missense	Exon 3 of 9	ENSP00000452453.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Benign	0.042
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.26
Sift	Benign	0.16	T
Sift4G	Benign	0.11	T
Polyphen		0.026	B
Vest4		0.87
MutPred		0.70		Gain of catalytic residue at T329 (P = 0.0102)
MVP		0.80
MPC		0.42
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.81
gMVP		0.94
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs757778790; hg19: chr14-76100017;