14-71588042-C-A

Position:

• chr14-71588042-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_001386936.1(SIPA1L1):​c.170C>A​(p.Pro57His) variant causes a missense change. The variant allele was found at a frequency of 0.000872 in 1,614,114 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (1 hom.)
• Consequence: SIPA1L1 NM_001386936.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.09

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0117173195).
• BP6: Variant 14-71588042-C-A is Benign according to our data. Variant chr14-71588042-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 777242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIPA1L1	NM_001386936.1	c.170C>A	p.Pro57His	missense_variant	5/24	ENST00000381232.8	NP_001373865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIPA1L1	ENST00000381232.8	c.170C>A	p.Pro57His	missense_variant	5/24	1	NM_001386936.1	ENSP00000370630	P4
SIPA1L1	ENST00000555818.5	c.170C>A	p.Pro57His	missense_variant	2/22	1		ENSP00000450832
	ENST00000647653.1	n.1320G>T		non_coding_transcript_exon_variant	2/2
SIPA1L1	ENST00000358550.6	c.170C>A	p.Pro57His	missense_variant	2/21	2		ENSP00000351352	A1

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000984 AC: 247 AN: 250966 Hom.: 1 AF XY: 0.00101 AC XY: 137 AN XY: 135666

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00481

Gnomad NFE exome AF: 0.00110

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000852 AC: 1246 AN: 1461820 Hom.: 1 Cov.: 30 AF XY: 0.000854 AC XY: 621 AN XY: 727216

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00412

Gnomad4 NFE exome AF: 0.000885

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.00106 AC: 161 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000967 AC XY: 72 AN XY: 74456

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000851 Hom.: 0

Bravo AF: 0.000699

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000782 AC: 95

EpiCase AF: 0.000873

EpiControl AF: 0.000889

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	SIPA1L1: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	.;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Uncertain	0.0084	D
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.94	P;D;.
Vest4		0.35
MVP		0.49
MPC		0.68
ClinPred		0.068	T
GERP RS		5.5
Varity_R		0.19
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs148958695; hg19: chr14-72054759;