12-63150429-A-T

Variant names:

• chr12-63150429-A-T
• rs1042615
• NM_000706.5:c.408T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000706.5(AVPR1A):​c.408T>A​(p.Phe136Leu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as (no stars). Synonymous variant affecting the same amino acid position (i.e. F136F) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000055 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AVPR1A NM_000706.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.93
• Publications: 59 publications found

Genes affected

AVPR1A (HGNC:895): (arginine vasopressin receptor 1A) The protein encoded by this gene acts as receptor for arginine vasopressin. This receptor belongs to the subfamily of G-protein coupled receptors which includes AVPR1B, V2R and OXT receptors. Its activity is mediated by G proteins which stimulate a phosphatidylinositol-calcium second messenger system. The receptor mediates cell contraction and proliferation, platelet aggregation, release of coagulation factor and glycogenolysis. [provided by RefSeq, Jul 2008]

AVPR1A Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000302777 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000706.5. 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
	AVPR1A	NM_000706.5	MANE Select	c.408T>A	p.Phe136Leu	missense	Exon 1 of 2	NP_000697.1	P37288

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AVPR1A	ENST00000299178.4	TSL:1 MANE Select	c.408T>A	p.Phe136Leu	missense	Exon 1 of 2	ENSP00000299178.3	P37288
	AVPR1A	ENST00000550940.1	TSL:3	c.-250T>A		upstream_gene	N/A	ENSP00000449822.1	F8VW98
	ENSG00000302777	ENST00000789494.1		n.-115A>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 247436 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000895

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000548 AC: 8 AN: 1460808 Hom.: 0 Cov.: 88 AF XY: 0.00000688 AC XY: 5 AN XY: 726688

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111556

Other (OTH) AF: 0.0000166 AC: 1 AN: 60358

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 26971

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.063	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		2.9
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.73		Gain of catalytic residue at A137 (P = 0.0013)
MVP		0.86
MPC		1.8
ClinPred		0.96	D
GERP RS		4.9
PromoterAI		-0.0097	Neutral
Varity_R		0.60
gMVP		0.67
Mutation Taster		=30/70	disease causing

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: rs1042615; hg19: chr12-63544209;