1-232415554-G-A

Variant names:

• chr1-232415554-G-A
• rs202124136
• NM_020808.5:c.4702C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020808.5(SIPA1L2):​c.4702C>T​(p.Pro1568Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,580 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. P1568A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SIPA1L2 NM_020808.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32
• Publications: 1 publications found

Genes affected

SIPA1L2 (HGNC:23800): (signal induced proliferation associated 1 like 2) This gene encodes a member of the signal-induced proliferation-associated 1 like family. Members of this family contain a GTPase activating domain, a PDZ domain and a C-terminal coiled-coil domain with a leucine zipper. A similar protein in rat acts as a GTPases for the small GTPase Rap. [provided by RefSeq, Sep 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIPA1L2	NM_020808.5	c.4702C>T	p.Pro1568Ser	missense_variant	Exon 19 of 23	ENST00000674635.1	NP_065859.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIPA1L2	ENST00000674635.1	c.4702C>T	p.Pro1568Ser	missense_variant	Exon 19 of 23		NM_020808.5	ENSP00000502693.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461580 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 727084

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111872

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000992 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;T;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Uncertain	2.9	M;M;.
PhyloP100		9.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.7	D;D;D
REVEL	Uncertain	0.62
Sift	Benign	0.032	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.87
MutPred		0.38		Gain of phosphorylation at P1568 (P = 0.0841);Gain of phosphorylation at P1568 (P = 0.0841);.;
MVP		0.63
MPC		0.72
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.40
gMVP		0.76
Mutation Taster		=55/45	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: rs202124136; hg19: chr1-232551300; COSMIC: COSV53391108;