rs7941523

Positions:

• chr11-124637123-G-A
• chr11-124637123-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_170601.5(SIAE):​c.1400C>T​(p.Ala467Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00561 in 1,614,100 control chromosomes in the GnomAD database, including 227 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.022 (109 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (118 hom.)
• Consequence: SIAE NM_170601.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.690

Genes affected

SIAE (HGNC:18187): (sialic acid acetylesterase) This gene encodes an enzyme which removes 9-O-acetylation modifications from sialic acids. Mutations in this gene are associated with susceptibility to autoimmune disease 6. Multiple transcript variants encoding different isoforms, found either in the cytosol or in the lysosome, have been found for this gene.[provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026714504).
• BP6: Variant 11-124637123-G-A is Benign according to our data. Variant chr11-124637123-G-A is described in ClinVar as [Benign]. Clinvar id is 776676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIAE	NM_170601.5	c.1400C>T	p.Ala467Val	missense_variant	10/10	ENST00000263593.8	NP_733746.1
SIAE	NM_001199922.2	c.1295C>T	p.Ala432Val	missense_variant	12/12		NP_001186851.1
SIAE	XM_047427132.1	c.827C>T	p.Ala276Val	missense_variant	7/7		XP_047283088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIAE	ENST00000263593.8	c.1400C>T	p.Ala467Val	missense_variant	10/10	1	NM_170601.5	ENSP00000263593.3
SIAE	ENST00000618733.4	c.1295C>T	p.Ala432Val	missense_variant	12/12	1		ENSP00000478211.1
SIAE	ENST00000545756.5	c.1295C>T	p.Ala432Val	missense_variant	11/11	5		ENSP00000437877.1

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3390 AN: 152094 Hom.: 109 Cov.: 32

Gnomad AFR AF: 0.0721

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00986

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.00870 AC: 2187 AN: 251472 Hom.: 65 AF XY: 0.00764 AC XY: 1039 AN XY: 135910

Gnomad AFR exome AF: 0.0780

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00714

Gnomad EAS exome AF: 0.0111

Gnomad SAS exome AF: 0.0113

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000598

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00387 AC: 5656 AN: 1461888 Hom.: 118 Cov.: 31 AF XY: 0.00388 AC XY: 2819 AN XY: 727244

Gnomad4 AFR exome AF: 0.0782

Gnomad4 AMR exome AF: 0.00624

Gnomad4 ASJ exome AF: 0.00784

Gnomad4 EAS exome AF: 0.0134

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000417

Gnomad4 OTH exome AF: 0.00868

GnomAD4 genome AF: 0.0223 AC: 3401 AN: 152212 Hom.: 109 Cov.: 32 AF XY: 0.0219 AC XY: 1626 AN XY: 74408

Gnomad4 AFR AF: 0.0722

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00988

Gnomad4 SAS AF: 0.0126

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00622 Hom.: 43

Bravo AF: 0.0261

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0666 AC: 293

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00985 AC: 1196

Asia WGS AF: 0.0240 AC: 84 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	This variant is associated with the following publications: (PMID: 24748456) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.4
DANN	Benign	0.95
DEOGEN2	Benign	0.067	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.61	T;T;.
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.88	N;N;.
REVEL	Benign	0.14
Sift	Benign	0.37	T;T;.
Sift4G	Benign	0.31	T;T;T
Polyphen		0.11	B;.;.
Vest4		0.066
MVP		0.21
MPC		0.14
ClinPred		0.00068	T
GERP RS		-0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs7941523; hg19: chr11-124507019;