12-53066438-C-T

Variant names:

• chr12-53066438-C-T
• rs372927015
• NM_032840.3:c.1070G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032840.3(SPRYD3):​c.1070G>A​(p.Arg357Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R357P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPRYD3 NM_032840.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.48

Genes affected

SPRYD3 (HGNC:25920): (SPRY domain containing 3) Predicted to be involved in cell surface receptor signaling pathway and cytoskeleton organization. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRYD3	NM_032840.3	c.1070G>A	p.Arg357Gln	missense_variant	Exon 10 of 11	ENST00000301463.9	NP_116229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRYD3	ENST00000301463.9	c.1070G>A	p.Arg357Gln	missense_variant	Exon 10 of 11	1	NM_032840.3	ENSP00000301463.4
SPRYD3	ENST00000547837.5	c.1181G>A	p.Arg394Gln	missense_variant	Exon 11 of 12	5		ENSP00000449452.1
SPRYD3	ENST00000547257.1	n.-80G>A		upstream_gene_variant		5		ENSP00000448845.1
SPRYD3	ENST00000537540.1	n.*522G>A		downstream_gene_variant		2		ENSP00000446156.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249472 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135012

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000895

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727246

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0026	T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.064
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.69	N;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.080	N;N
REVEL	Benign	0.078
Sift	Benign	0.49	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.30	B;.
Vest4		0.43
MutPred		0.47		Gain of catalytic residue at V362 (P = 0.021);.;
MVP		0.10
MPC		0.91
ClinPred		0.29	T
GERP RS		4.9
Varity_R		0.061
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs372927015; hg19: chr12-53460222;