NM_001270616.2:c.692A>G

Variant names:

• chr1-213997227-A-G
• rs1663300911
• NM_001270616.2:c.692A>G

Variant summary

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

The NM_001270616.2(PROX1):​c.692A>G​(p.Gln231Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PROX1 NM_001270616.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.21
• Publications: 0 publications found

Genes affected

PROX1 (HGNC:9459): (prospero homeobox 1) The protein encoded by this gene is a member of the homeobox transcription factor family. Members of this family contain a homeobox domain that consists of a 60-amino acid helix-turn-helix structure that binds DNA and RNA. The protein encoded by this gene is conserved across vertebrates and may play an essential role during development. Altered levels of this protein have been reported in cancers of different organs, such as colon, brain, blood, breast, pancreas, liver and esophagus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

PROX1 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD 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=0.3865637).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270616.2. 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
	PROX1	NM_001270616.2	MANE Select	c.692A>G	p.Gln231Arg	missense	Exon 2 of 5	NP_001257545.1	Q92786
	PROX1	NM_002763.5		c.692A>G	p.Gln231Arg	missense	Exon 2 of 5	NP_002754.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROX1	ENST00000366958.9	TSL:1 MANE Select	c.692A>G	p.Gln231Arg	missense	Exon 2 of 5	ENSP00000355925.4	Q92786
	PROX1	ENST00000435016.2	TSL:1	c.692A>G	p.Gln231Arg	missense	Exon 2 of 5	ENSP00000400694.1	Q92786
	PROX1	ENST00000881021.1		c.692A>G	p.Gln231Arg	missense	Exon 2 of 5	ENSP00000551080.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.0043	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		6.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.18
Sift	Benign	0.42	T
Sift4G	Benign	0.52	T
Polyphen		0.98	D
Vest4		0.40
MutPred		0.50		Loss of methylation at K232 (P = 0.0939)
MVP		0.76
MPC		1.5
ClinPred		0.84	D
GERP RS		5.9
Varity_R		0.33
gMVP		0.37
Mutation Taster		=42/58	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: rs1663300911; hg19: chr1-214170570;