19-38395505-C-T

Variant names:

• chr19-38395505-C-T
• rs377606661
• NM_001394336.1:c.593C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394336.1(SPRED3):​c.593C>T​(p.Thr198Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,518,210 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: SPRED3 NM_001394336.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18414325).

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.593C>T	p.Thr198Met	missense	Exon 6 of 6	NP_001381265.1	Q2MJR0-1
	SPRED3	NM_001042522.3		c.593C>T	p.Thr198Met	missense	Exon 5 of 5	NP_001035987.1	Q2MJR0-1
	SPRED3	NM_001394337.1		c.449C>T	p.Thr150Met	missense	Exon 5 of 5	NP_001381266.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRED3	ENST00000691638.1	MANE Select	c.593C>T	p.Thr198Met	missense	Exon 6 of 6	ENSP00000510478.1	Q2MJR0-1
	SPRED3	ENST00000338502.8	TSL:1	c.593C>T	p.Thr198Met	missense	Exon 5 of 5	ENSP00000345405.4	Q2MJR0-1
	SPRED3	ENST00000587013.6	TSL:5	c.725C>T	p.Thr242Met	missense	Exon 5 of 5	ENSP00000467540.1	K7EPU5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000678 AC: 1 AN: 147556 AF XY: 0.0000123

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 20 AN: 1366004 Hom.: 0 Cov.: 31 AF XY: 0.0000207 AC XY: 14 AN XY: 675178

African (AFR) AF: 0.0000361 AC: 1 AN: 27730

American (AMR) AF: 0.00 AC: 0 AN: 28636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21628

East Asian (EAS) AF: 0.00 AC: 0 AN: 32728

South Asian (SAS) AF: 0.00 AC: 0 AN: 73620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5470

European-Non Finnish (NFE) AF: 0.0000178 AC: 19 AN: 1069780

Other (OTH) AF: 0.00 AC: 0 AN: 56020

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000337 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.00000832 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.029
Eigen_PC	Benign	-0.027
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.29
Sift	Benign	0.11	T
Sift4G	Benign	0.082	T
Polyphen		1.0	D
Vest4		0.12
MVP		0.84
MPC		0.73
ClinPred		0.27	T
GERP RS		3.4
Varity_R		0.038
gMVP		0.36
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs377606661; hg19: chr19-38886145;