19-38395546-G-A

Variant names:

• chr19-38395546-G-A
• NM_001394336.1:c.634G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394336.1(SPRED3):​c.634G>A​(p.Gly212Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000428 in 1,400,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000043 (0 hom.)
• Consequence: SPRED3 NM_001394336.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.222

Genes affected

SPRED3 (HGNC:31041): (sprouty related EVH1 domain containing 3) This gene encodes a protein with a C-terminal Sprouty-like cysteine-rich domain (SRY) and an N-terminal Ena/Vasodilator-stimulated phosphoprotein (VASP) homology-1 (EVH-1) domain. The encoded protein is a member of a family of proteins that negatively regulates mitogen-activated protein (MAP) kinase signaling, particularly during organogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13696343).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRED3	NM_001394336.1	c.634G>A	p.Gly212Ser	missense_variant	Exon 6 of 6	ENST00000691638.1	NP_001381265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRED3	ENST00000691638.1	c.634G>A	p.Gly212Ser	missense_variant	Exon 6 of 6		NM_001394336.1	ENSP00000510478.1
SPRED3	ENST00000338502.8	c.634G>A	p.Gly212Ser	missense_variant	Exon 5 of 5	1		ENSP00000345405.4
SPRED3	ENST00000587013.6	c.766G>A	p.Gly256Ser	missense_variant	Exon 5 of 5	5		ENSP00000467540.1
SPRED3	ENST00000586301.6	c.634G>A	p.Gly212Ser	missense_variant	Exon 6 of 6	5		ENSP00000466568.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000428 AC: 6 AN: 1400446 Hom.: 0 Cov.: 31 AF XY: 0.00000721 AC XY: 5 AN XY: 693534

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: 0.00000553

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.634G>A (p.G212S) alteration is located in exon 5 (coding exon 5) of the SPRED3 gene. This alteration results from a G to A substitution at nucleotide position 634, causing the glycine (G) at amino acid position 212 to be replaced by a serine (S). 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	0.072
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.0038	.;T;T
Eigen	Benign	0.011
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.70	T;.;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.0	.;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.20	.;.;N
REVEL	Benign	0.23
Sift	Benign	0.68	.;.;T
Sift4G	Benign	0.77	T;T;T
Polyphen		1.0	.;D;D
Vest4		0.11
MutPred		0.24		.;Gain of glycosylation at G212 (P = 0.0248);Gain of glycosylation at G212 (P = 0.0248);
MVP		0.80
MPC		0.26
ClinPred		0.18	T
GERP RS		1.8
Varity_R		0.035
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-38886186;