19-38390376-G-C

Variant names:

• chr19-38390376-G-C
• rs768473164
• NM_001394336.1:c.74G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001394336.1(SPRED3):​c.74G>C​(p.Gly25Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G25V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: SPRED3 NM_001394336.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.90
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394336.1. 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
	SPRED3	NM_001394336.1	MANE Select	c.74G>C	p.Gly25Ala	missense	Exon 2 of 6	NP_001381265.1	Q2MJR0-1
	SPRED3	NM_001042522.3		c.74G>C	p.Gly25Ala	missense	Exon 1 of 5	NP_001035987.1	Q2MJR0-1
	SPRED3	NM_001394337.1		c.74G>C	p.Gly25Ala	missense	Exon 2 of 5	NP_001381266.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRED3	ENST00000691638.1	MANE Select	c.74G>C	p.Gly25Ala	missense	Exon 2 of 6	ENSP00000510478.1	Q2MJR0-1
	SPRED3	ENST00000338502.8	TSL:1	c.74G>C	p.Gly25Ala	missense	Exon 1 of 5	ENSP00000345405.4	Q2MJR0-1
	SPRED3	ENST00000587564.2	TSL:1	n.78G>C		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.7	L
PhyloP100		9.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.69
Sift	Benign	0.081	T
Sift4G	Uncertain	0.032	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.49		Gain of sheet (P = 0.0149)
MVP		0.94
MPC		0.75
ClinPred		0.99	D
GERP RS		4.0
PromoterAI		-0.024	Neutral
Varity_R		0.62
gMVP		0.54
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs768473164; hg19: chr19-38881016;