19-38390478-A-G

Variant names:

• chr19-38390478-A-G
• rs780141379
• NM_001394336.1:c.176A>G

Variant summary

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

The NM_001394336.1(SPRED3):​c.176A>G​(p.Lys59Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 1,365,146 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: 30)
  • Exomes 𝑓: 0.0000066 (0 hom.)
• Consequence: SPRED3 NM_001394336.1 missense, splice_region
• Scores: Splicing: ADA: 0.9496
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06
• Publications: 1 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 2 ACMG points.

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

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.176A>G	p.Lys59Arg	missense splice_region	Exon 2 of 6	NP_001381265.1	Q2MJR0-1
	SPRED3	NM_001042522.3		c.176A>G	p.Lys59Arg	missense splice_region	Exon 1 of 5	NP_001035987.1	Q2MJR0-1
	SPRED3	NM_001394337.1		c.176A>G	p.Lys59Arg	missense splice_region	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.176A>G	p.Lys59Arg	missense splice_region	Exon 2 of 6	ENSP00000510478.1	Q2MJR0-1
	SPRED3	ENST00000338502.8	TSL:1	c.176A>G	p.Lys59Arg	missense splice_region	Exon 1 of 5	ENSP00000345405.4	Q2MJR0-1
	SPRED3	ENST00000587564.2	TSL:1	n.180A>G		splice_region non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151868 Hom.: 0 Cov.: 30

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

GnomAD4 exome AF: 0.00000659 AC: 8 AN: 1213278 Hom.: 0 Cov.: 32 AF XY: 0.00000678 AC XY: 4 AN XY: 590192

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24104

American (AMR) AF: 0.00 AC: 0 AN: 10360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18982

East Asian (EAS) AF: 0.00 AC: 0 AN: 27782

South Asian (SAS) AF: 0.00 AC: 0 AN: 46844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4234

European-Non Finnish (NFE) AF: 0.00000709 AC: 7 AN: 987700

Other (OTH) AF: 0.0000203 AC: 1 AN: 49212

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000021002), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151868 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74166

African (AFR) AF: 0.00 AC: 0 AN: 41332

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67904

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000891 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	0.12
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.042
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	0.55	N
PhyloP100		1.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.51	N
REVEL	Uncertain	0.40
Sift	Benign	0.70	T
Sift4G	Benign	0.57	T
Polyphen		0.96	D
Vest4		0.41
MutPred		0.28		Loss of ubiquitination at K59 (P = 0.0167)
MVP		0.91
MPC		0.27
ClinPred		0.41	T
GERP RS		3.1
PromoterAI		0.0067	Neutral
Varity_R		0.054
gMVP		0.26
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.75
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.23		Position offset: 1

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

Other links and lift over

dbSNP: rs780141379; hg19: chr19-38881118;