NM_001029871.4:c.194A>T

Variant names:

• chr20-968024-T-A
• NM_001029871.4:c.194A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001029871.4(RSPO4):​c.194A>T​(p.Gln65Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q65R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RSPO4 NM_001029871.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.53

Genes affected

RSPO4 (HGNC:16175): (R-spondin 4) This gene encodes a member of the R-spondin family of proteins that share a common domain organization consisting of a signal peptide, cysteine-rich/furin-like domain, thrombospondin domain and a C-terminal basic region. The encoded protein may be involved in activation of Wnt/beta-catenin signaling pathways. Mutations in this gene are associated with anonychia congenital. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-968024-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPO4	NM_001029871.4	c.194A>T	p.Gln65Leu	missense_variant	Exon 2 of 5	ENST00000217260.9	NP_001025042.2
RSPO4	NM_001040007.3	c.194A>T	p.Gln65Leu	missense_variant	Exon 2 of 4		NP_001035096.1
RSPO4	XM_017027839.2	c.194A>T	p.Gln65Leu	missense_variant	Exon 2 of 4		XP_016883328.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPO4	ENST00000217260.9	c.194A>T	p.Gln65Leu	missense_variant	Exon 2 of 5	1	NM_001029871.4	ENSP00000217260.4
RSPO4	ENST00000400634.2	c.194A>T	p.Gln65Leu	missense_variant	Exon 2 of 4	1		ENSP00000383475.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.84
MutPred		0.75		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.88
MPC		0.34
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.68
gMVP		0.60

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: chr20-948667;