1-11706473-C-G

Variant names:

• chr1-11706473-C-G
• rs374833602
• NM_198545.4:c.215C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_198545.4(DRAXIN):​c.215C>G​(p.Pro72Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,458,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: DRAXIN NM_198545.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.23

Genes affected

DRAXIN (HGNC:25054): (dorsal inhibitory axon guidance protein) Predicted to be involved in negative regulation of canonical Wnt signaling pathway; negative regulation of neuron projection development; and nervous system development. Predicted to act upstream of or within negative regulation of axon extension and negative regulation of neuron apoptotic process. Predicted to be active in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27655956).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRAXIN	NM_198545.4	c.215C>G	p.Pro72Arg	missense_variant	Exon 2 of 7	ENST00000294485.6	NP_940947.3
DRAXIN	XM_017001215.2	c.449C>G	p.Pro150Arg	missense_variant	Exon 3 of 4		XP_016856704.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRAXIN	ENST00000294485.6	c.215C>G	p.Pro72Arg	missense_variant	Exon 2 of 7	1	NM_198545.4	ENSP00000294485.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1458464 Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3 AN XY: 725416

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.215C>G (p.P72R) alteration is located in exon 2 (coding exon 1) of the DRAXIN gene. This alteration results from a C to G substitution at nucleotide position 215, causing the proline (P) at amino acid position 72 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.075
Eigen_PC	Benign	-0.092
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.15
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.076	T
Polyphen		1.0	D
Vest4		0.39
MVP		0.45
MPC		0.85
ClinPred		0.91	D
GERP RS		4.5
Varity_R		0.21
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs374833602; hg19: chr1-11766530;