1-230979107-T-G

Variant names:

• chr1-230979107-T-G
• rs774445829
• NM_022786.3:c.2T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_022786.3(ARV1):​c.2T>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARV1 NM_022786.3 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.900
• 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]

TTC13 (HGNC:26204): (tetratricopeptide repeat domain 13)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 6 pathogenic variants. Next in-frame start position is after 143 codons. Genomic position: 230990242. Lost 0.523 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.2T>G	p.Met1?	start_lost	Exon 1 of 6	NP_073623.1	Q9H2C2
	ARV1	NM_001346992.2		c.2T>G	p.Met1?	start_lost	Exon 1 of 7	NP_001333921.1
	ARV1	NR_144538.2		n.14T>G		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARV1	ENST00000310256.7	TSL:1 MANE Select	c.2T>G	p.Met1?	start_lost	Exon 1 of 6	ENSP00000312458.2	Q9H2C2
	ARV1	ENST00000893839.1		c.2T>G	p.Met1?	start_lost	Exon 1 of 7	ENSP00000563898.1
	ARV1	ENST00000893842.1		c.2T>G	p.Met1?	start_lost	Exon 1 of 6	ENSP00000563901.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455734 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724044

African (AFR) AF: 0.00 AC: 0 AN: 33112

American (AMR) AF: 0.00 AC: 0 AN: 43708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25876

East Asian (EAS) AF: 0.00 AC: 0 AN: 39282

South Asian (SAS) AF: 0.00 AC: 0 AN: 85678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5368

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109706

Other (OTH) AF: 0.00 AC: 0 AN: 60090

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-1.0	T
PhyloP100		0.90
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.26
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.0	B
Vest4		0.66
MutPred		0.99		Gain of methylation at M1 (P = 0.0019)
MVP		0.73
ClinPred		0.98	D
GERP RS		3.6
PromoterAI		-0.0092	Neutral
Varity_R		0.95
gMVP		0.85
Mutation Taster		=53/147	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: rs774445829; hg19: chr1-231114853;