chr19-38390455-C-A

Variant names:

• chr19-38390455-C-A
• rs370701407
• NM_001394336.1:c.153C>A

Variant summary

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

The NM_001394336.1(SPRED3):​c.153C>A​(p.His51Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000091 in 1,098,892 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H51H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 9.1e-7 (0 hom.)
• Consequence: SPRED3 NM_001394336.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.627
• 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 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.153C>A	p.His51Gln	missense	Exon 2 of 6	NP_001381265.1	Q2MJR0-1
	SPRED3	NM_001042522.3		c.153C>A	p.His51Gln	missense	Exon 1 of 5	NP_001035987.1	Q2MJR0-1
	SPRED3	NM_001394337.1		c.153C>A	p.His51Gln	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.153C>A	p.His51Gln	missense	Exon 2 of 6	ENSP00000510478.1	Q2MJR0-1
	SPRED3	ENST00000338502.8	TSL:1	c.153C>A	p.His51Gln	missense	Exon 1 of 5	ENSP00000345405.4	Q2MJR0-1
	SPRED3	ENST00000587564.2	TSL:1	n.157C>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 9.10e-7 AC: 1 AN: 1098892 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 534368

⚠️ 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: 20464

American (AMR) AF: 0.00 AC: 0 AN: 8434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14134

East Asian (EAS) AF: 0.00 AC: 0 AN: 18728

South Asian (SAS) AF: 0.00 AC: 0 AN: 47408

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3936

European-Non Finnish (NFE) AF: 0.00000109 AC: 1 AN: 913440

Other (OTH) AF: 0.00 AC: 0 AN: 40584

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	0.17
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.63
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.029	D
Sift4G	Benign	0.18	T
Polyphen		0.91	P
Vest4		0.58
MutPred		0.50		Gain of MoRF binding (P = 0.0862)
MVP		0.85
MPC		0.93
ClinPred		0.97	D
GERP RS		3.0
PromoterAI		0.0062	Neutral
Varity_R		0.43
gMVP		0.37
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs370701407; hg19: chr19-38881095;