1-230988428-A-T

Variant names:

• chr1-230988428-A-T
• rs146498592
• NM_022786.3:c.283A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_022786.3(ARV1):​c.283A>T​(p.Thr95Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. T95P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARV1 NM_022786.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.90
• Publications: 0 publications found

Genes affected

ARV1 (HGNC:29561): (ARV1 homolog, fatty acid homeostasis modulator) this gene encodes a transmembrane protein that contains a conserved zinc ribbon motif at the N- terminus. A similar protein in mouse is thought to function in fatty acid homeostasis. Mutations in this gene are associated with early infantile epileptic encephalopathy 38. [provided by RefSeq, Nov 2016]

ARV1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 38

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022786.3. 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
	ARV1	NM_022786.3	MANE Select	c.283A>T	p.Thr95Ser	missense	Exon 2 of 6	NP_073623.1	Q9H2C2
	ARV1	NM_001346992.2		c.283A>T	p.Thr95Ser	missense	Exon 2 of 7	NP_001333921.1
	ARV1	NR_144538.2		n.295A>T		non_coding_transcript_exon	Exon 2 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARV1	ENST00000310256.7	TSL:1 MANE Select	c.283A>T	p.Thr95Ser	missense	Exon 2 of 6	ENSP00000312458.2	Q9H2C2
	ARV1	ENST00000893839.1		c.283A>T	p.Thr95Ser	missense	Exon 2 of 7	ENSP00000563898.1
	ARV1	ENST00000893842.1		c.283A>T	p.Thr95Ser	missense	Exon 2 of 6	ENSP00000563901.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		8.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.28
Sift	Benign	0.18	T
Sift4G	Benign	0.72	T
Polyphen		0.86	P
Vest4		0.77
MutPred		0.47		Loss of helix (P = 0.1299)
MVP		0.83
MPC		0.37
ClinPred		0.88	D
GERP RS		4.9
Varity_R		0.18
gMVP		0.59
Mutation Taster		=70/30	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: rs146498592; hg19: chr1-231124174;