5-90689929-A-C

Variant names:

• chr5-90689929-A-C
• NM_032119.4:c.6559A>C
• ADGRV1 p.Ile2187Leu

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032119.4(ADGRV1):​c.6559A>C​(p.Ile2187Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. I2187V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.05
• Publications: 0 publications found

Genes affected

ADGRV1 (HGNC:17416): (adhesion G protein-coupled receptor V1) This gene encodes a member of the G-protein coupled receptor superfamily. The encoded protein contains a 7-transmembrane receptor domain, binds calcium and is expressed in the central nervous system. Mutations in this gene are associated with Usher syndrome 2 and familial febrile seizures. Several alternatively spliced transcripts have been described. [provided by RefSeq, Jul 2008]

ADGRV1 Gene-Disease associations (from GenCC):

• Usher syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 2C

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• febrile seizures, familial, 4

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33152482).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032119.4. 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
	ADGRV1	NM_032119.4	MANE Select	c.6559A>C	p.Ile2187Leu	missense	Exon 30 of 90	NP_115495.3	Q8WXG9-1
	ADGRV1	NR_003149.2		n.6658A>C		non_coding_transcript_exon	Exon 30 of 90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.6559A>C	p.Ile2187Leu	missense	Exon 30 of 90	ENSP00000384582.2	Q8WXG9-1
	ADGRV1	ENST00000640403.1	TSL:5	c.3850A>C	p.Ile1284Leu	missense	Exon 20 of 29	ENSP00000492531.1	A0A1W2PRC7
	ADGRV1	ENST00000639473.1	TSL:5	n.2018A>C		non_coding_transcript_exon	Exon 10 of 23

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.0
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Benign	0.14	T
Sift4G	Uncertain	0.016	D
Varity_R		0.15
gMVP		0.61
Mutation Taster		=65/35	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-89985746;