14-71588042-C-T

Variant names:

• chr14-71588042-C-T
• rs148958695
• NM_001386936.1:c.170C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001386936.1(SIPA1L1):​c.170C>T​(p.Pro57Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P57H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SIPA1L1 NM_001386936.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.09
• Publications: 4 publications found

Genes affected

SIPA1L1 (HGNC:20284): (signal induced proliferation associated 1 like 1) Predicted to enable GTPase activator activity; actin filament binding activity; and protein kinase binding activity. Predicted to be involved in several processes, including actin cytoskeleton organization; activation of GTPase activity; and regulation of postsynapse organization. Located in actin cytoskeleton and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000285612 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27041548).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386936.1. 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
	SIPA1L1	NM_001386936.1	MANE Select	c.170C>T	p.Pro57Leu	missense	Exon 5 of 24	NP_001373865.1	O43166-2
	SIPA1L1	NM_001354285.2		c.170C>T	p.Pro57Leu	missense	Exon 5 of 25	NP_001341214.1	O43166-1
	SIPA1L1	NM_015556.4		c.170C>T	p.Pro57Leu	missense	Exon 7 of 27	NP_056371.1	O43166-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIPA1L1	ENST00000381232.8	TSL:1 MANE Select	c.170C>T	p.Pro57Leu	missense	Exon 5 of 24	ENSP00000370630.3	O43166-2
	SIPA1L1	ENST00000555818.5	TSL:1	c.170C>T	p.Pro57Leu	missense	Exon 2 of 22	ENSP00000450832.1	O43166-1
	SIPA1L1	ENST00000962884.1		c.170C>T	p.Pro57Leu	missense	Exon 4 of 25	ENSP00000632943.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461820 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.0	L
PhyloP100		4.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.046	D
Polyphen		0.0090	B
Vest4		0.14
MutPred		0.18		Loss of catalytic residue at P56 (P = 0.0103)
MVP		0.34
MPC		0.34
ClinPred		0.86	D
GERP RS		5.5
Varity_R		0.097
gMVP		0.41
Mutation Taster		=93/7	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: rs148958695; hg19: chr14-72054759;