12-53073441-C-T

Variant names:

• chr12-53073441-C-T
• NM_032840.3:c.538G>A

Variant summary

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

The NM_032840.3(SPRYD3):​c.538G>A​(p.Asp180Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000708 in 1,412,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SPRYD3 NM_032840.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.74

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.538G>A	p.Asp180Asn	missense_variant	Exon 6 of 11	ENST00000301463.9	NP_116229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRYD3	ENST00000301463.9	c.538G>A	p.Asp180Asn	missense_variant	Exon 6 of 11	1	NM_032840.3	ENSP00000301463.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1412300 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 697006

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: 9.22e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 09, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.538G>A (p.D180N) alteration is located in exon 6 (coding exon 6) of the SPRYD3 gene. This alteration results from a G to A substitution at nucleotide position 538, causing the aspartic acid (D) at amino acid position 180 to be replaced by an asparagine (N). 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	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0040	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.18	N;N
REVEL	Benign	0.080
Sift	Benign	0.64	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.0020	B;.
Vest4		0.30
MutPred		0.43		Gain of catalytic residue at S178 (P = 0.0021);.;
MVP		0.27
MPC		0.98
ClinPred		0.90	D
GERP RS		5.2
Varity_R		0.22
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.44		Position offset: -16

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-53467225; COSMIC: COSV105013227;