chr14-71588618-C-T

Position:

• chr14-71588618-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001386936.1(SIPA1L1):​c.746C>T​(p.Thr249Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000351 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: SIPA1L1 NM_001386936.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.50

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04774037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIPA1L1	NM_001386936.1	c.746C>T	p.Thr249Ile	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.746C>T	p.Thr249Ile	missense_variant	5/24	1	NM_001386936.1	ENSP00000370630	P4
SIPA1L1	ENST00000555818.5	c.746C>T	p.Thr249Ile	missense_variant	2/22	1		ENSP00000450832
	ENST00000647653.1	n.744G>A		non_coding_transcript_exon_variant	2/2
SIPA1L1	ENST00000358550.6	c.746C>T	p.Thr249Ile	missense_variant	2/21	2		ENSP00000351352	A1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000160 AC: 40 AN: 250302 Hom.: 0 AF XY: 0.000200 AC XY: 27 AN XY: 135248

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000293

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000369 AC: 540 AN: 1461798 Hom.: 0 Cov.: 30 AF XY: 0.000334 AC XY: 243 AN XY: 727204

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000465

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74322

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000308 Hom.: 0

Bravo AF: 0.000174

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.0000545

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2024

The c.746C>T (p.T249I) alteration is located in exon 2 (coding exon 1) of the SIPA1L1 gene. This alteration results from a C to T substitution at nucleotide position 746, causing the threonine (T) at amino acid position 249 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.032	.;T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.048	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;N
MutationTaster	Benign	0.94	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.79	N;N;N
REVEL	Benign	0.043
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.0020	B;B;.
Vest4		0.093
MVP		0.22
MPC		0.37
ClinPred		0.030	T
GERP RS		5.2
Varity_R		0.035
gMVP		0.13

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: rs149278828; hg19: chr14-72055335;