Variant 11-406441-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001135054.2(SIGIRR):c.977A>G(p.Asp326Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,612,752 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D326E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 1 hom., cov: 34)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

SIGIRR
NM_001135054.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.90

Variant links:

Genes affected

SIGIRR (HGNC:30575): (single Ig and TIR domain containing) Predicted to enable NAD+ nucleosidase activity. Involved in negative regulation of DNA-binding transcription factor activity. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

SIGIRR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.02274549).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGIRR	NM_001135054.2 linkuse as main transcript	c.977A>G	p.Asp326Gly	missense_variant	9/10	ENST00000431843.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGIRR	ENST00000431843.7 linkuse as main transcript	c.977A>G	p.Asp326Gly	missense_variant	9/10	1	NM_001135054.2	P1	Q6IA17-1

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000940

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000762

AC:

AN:

249306

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

135402

show subpopulations

Gnomad AFR exome

AF:

0.00118

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1460392

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726478

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000256

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000406

Hom.:

Bravo

AF:

0.000295

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2023

The c.977A>G (p.D326G) alteration is located in exon 9 (coding exon 8) of the SIGIRR gene. This alteration results from a A to G substitution at nucleotide position 977, causing the aspartic acid (D) at amino acid position 326 to be replaced by a glycine (G). 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

0.082

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

T;T;T;T

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.74

M_CAP

Benign

0.021

MetaRNN

Benign

0.023

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.5

L;L;L;.

MutationTaster

Benign

0.99

D;D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.0

D;D;D;D

REVEL

Benign

0.044

Sift

Benign

0.11

T;T;T;D

Sift4G

Benign

0.13

T;T;T;T

Polyphen

0.058

B;B;B;B

Vest4

0.18

MVP

0.46

MPC

0.32

ClinPred

0.052

GERP RS

1.8

Varity_R

0.25

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over