1-232428542-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_020808.5(SIPA1L2):c.4279A>C(p.Met1427Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00767 in 1,585,292 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0057 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0079 (67 hom.)
• Consequence: SIPA1L2 NM_020808.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0920

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005518347).
• BP6: Variant 1-232428542-T-G is Benign according to our data. Variant chr1-232428542-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2640082.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIPA1L2	NM_020808.5	c.4279A>C	p.Met1427Leu	missense_variant	17/23	ENST00000674635.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIPA1L2	ENST00000674635.1	c.4279A>C	p.Met1427Leu	missense_variant	17/23		NM_020808.5	A1

Frequencies

GnomAD3 genomes AF: 0.00572 AC: 870 AN: 152024 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00557

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00932

Gnomad OTH AF: 0.00576

GnomAD3 exomes AF: 0.00580 AC: 1297 AN: 223572 Hom.: 14 AF XY: 0.00579 AC XY: 704 AN XY: 121592

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.00352

Gnomad ASJ exome AF: 0.00165

Gnomad EAS exome AF: 0.000126

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.00779

Gnomad NFE exome AF: 0.00881

Gnomad OTH exome AF: 0.00803

GnomAD4 exome AF: 0.00788 AC: 11296 AN: 1433150 Hom.: 67 Cov.: 33 AF XY: 0.00779 AC XY: 5547 AN XY: 712206

Gnomad4 AFR exome AF: 0.00145

Gnomad4 AMR exome AF: 0.00344

Gnomad4 ASJ exome AF: 0.00166

Gnomad4 EAS exome AF: 0.0000522

Gnomad4 SAS exome AF: 0.00145

Gnomad4 FIN exome AF: 0.00742

Gnomad4 NFE exome AF: 0.00918

Gnomad4 OTH exome AF: 0.00759

GnomAD4 genome AF: 0.00571 AC: 869 AN: 152142 Hom.: 5 Cov.: 31 AF XY: 0.00544 AC XY: 405 AN XY: 74386

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00582

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00250

Gnomad4 FIN AF: 0.00557

Gnomad4 NFE AF: 0.00931

Gnomad4 OTH AF: 0.00570

Alfa AF: 0.00769 Hom.: 8

Bravo AF: 0.00511

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00361 AC: 14

ESP6500EA AF: 0.00880 AC: 73

ExAC AF: 0.00515 AC: 623

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

SIPA1L2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	5.6
Dann	Benign	0.38
DEOGEN2	Benign	0.017	T;T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.35	N
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.0055	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.64	N;N;N
REVEL	Benign	0.074
Sift	Benign	0.31	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.085
MutPred		0.24		Loss of disorder (P = 0.0664);Loss of disorder (P = 0.0664);.;
MVP		0.068
MPC		0.16
ClinPred		0.0027	T
GERP RS		-2.9
Varity_R		0.078
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs61729754; hg19: chr1-232564288; COSMIC: COSV99035439;