chr4-87491654-T-A

Variant names:

• chr4-87491654-T-A
• rs1130643
• NM_004684.6:c.1255A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004684.6(SPARCL1):​c.1255A>T​(p.Thr419Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPARCL1 NM_004684.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.251
• Publications: 26 publications found

Genes affected

SPARCL1 (HGNC:11220): (SPARC like 1) Predicted to enable calcium ion binding activity; collagen binding activity; and extracellular matrix binding activity. Predicted to be involved in anatomical structure development and regulation of synapse organization. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

SPARCL1 Gene-Disease associations (from GenCC):

• stromal corneal dystrophy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.024223894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPARCL1	NM_004684.6	c.1255A>T	p.Thr419Ser	missense_variant	Exon 5 of 11	ENST00000282470.11	NP_004675.3
SPARCL1	NM_001128310.3	c.1255A>T	p.Thr419Ser	missense_variant	Exon 6 of 12		NP_001121782.1
SPARCL1	NM_001291976.2	c.880A>T	p.Thr294Ser	missense_variant	Exon 6 of 12		NP_001278905.1
SPARCL1	NM_001291977.2	c.880A>T	p.Thr294Ser	missense_variant	Exon 4 of 10		NP_001278906.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPARCL1	ENST00000282470.11	c.1255A>T	p.Thr419Ser	missense_variant	Exon 5 of 11	1	NM_004684.6	ENSP00000282470.6
SPARCL1	ENST00000418378.5	c.1255A>T	p.Thr419Ser	missense_variant	Exon 6 of 12	5		ENSP00000414856.1
SPARCL1	ENST00000503414.5	c.880A>T	p.Thr294Ser	missense_variant	Exon 6 of 12	2		ENSP00000422903.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.017
DANN	Benign	0.17
DEOGEN2	Benign	0.023	T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.29	.;T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.024	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.42	N;N;.
PhyloP100		-0.25
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.050	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.89	T;T;T
Sift4G	Benign	0.82	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.054
MutPred		0.18		Gain of phosphorylation at T419 (P = 0.0438);Gain of phosphorylation at T419 (P = 0.0438);.;
MVP		0.17
MPC		0.069
ClinPred		0.030	T
GERP RS		-4.3
Varity_R		0.033
gMVP		0.17
Mutation Taster		=98/2	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: rs1130643; hg19: chr4-88412806;