11-406483-T-C

Variant names:

• chr11-406483-T-C
• rs3210908
• NM_001135054.2:c.935A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001135054.2(SIGIRR):​c.935A>G​(p.Gln312Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.789 in 1,612,348 control chromosomes in the GnomAD database, including 506,780 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.84 (54089 hom., cov: 38)
  • Exomes 𝑓: 0.78 (452691 hom.)
• Consequence: SIGIRR NM_001135054.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0160
• Publications: 52 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3141491E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135054.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGIRR	NM_001135054.2	MANE Select	c.935A>G	p.Gln312Arg	missense	Exon 9 of 10	NP_001128526.1
	SIGIRR	NM_001135053.2		c.935A>G	p.Gln312Arg	missense	Exon 9 of 10	NP_001128525.1
	SIGIRR	NM_021805.3		c.935A>G	p.Gln312Arg	missense	Exon 9 of 10	NP_068577.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGIRR	ENST00000431843.7	TSL:1 MANE Select	c.935A>G	p.Gln312Arg	missense	Exon 9 of 10	ENSP00000403104.2
	SIGIRR	ENST00000397632.7	TSL:1	c.935A>G	p.Gln312Arg	missense	Exon 9 of 10	ENSP00000380756.3
	SIGIRR	ENST00000531205.5	TSL:2	c.935A>G	p.Gln312Arg	missense	Exon 8 of 8	ENSP00000433022.1

Frequencies

GnomAD3 genomes AF: 0.837 AC: 127292 AN: 152006 Hom.: 54025 Cov.: 38

Gnomad AFR AF: 0.953

Gnomad AMI AF: 0.857

Gnomad AMR AF: 0.867

Gnomad ASJ AF: 0.883

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.944

Gnomad FIN AF: 0.726

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.755

Gnomad OTH AF: 0.848

GnomAD2 exomes AF: 0.838 AC: 208118 AN: 248432 AF XY: 0.837

Gnomad AFR exome AF: 0.959

Gnomad AMR exome AF: 0.919

Gnomad ASJ exome AF: 0.883

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.723

Gnomad NFE exome AF: 0.756

Gnomad OTH exome AF: 0.832

GnomAD4 exome AF: 0.784 AC: 1144337 AN: 1460224 Hom.: 452691 Cov.: 74 AF XY: 0.789 AC XY: 572812 AN XY: 726394

African (AFR) AF: 0.960 AC: 32133 AN: 33478

American (AMR) AF: 0.914 AC: 40887 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.880 AC: 22980 AN: 26126

East Asian (EAS) AF: 1.00 AC: 39677 AN: 39696

South Asian (SAS) AF: 0.945 AC: 81544 AN: 86256

European-Finnish (FIN) AF: 0.727 AC: 37859 AN: 52074

Middle Eastern (MID) AF: 0.907 AC: 5226 AN: 5762

European-Non Finnish (NFE) AF: 0.751 AC: 834702 AN: 1111768

Other (OTH) AF: 0.817 AC: 49329 AN: 60348

GnomAD4 genome AF: 0.838 AC: 127415 AN: 152124 Hom.: 54089 Cov.: 38 AF XY: 0.840 AC XY: 62462 AN XY: 74348

African (AFR) AF: 0.953 AC: 39602 AN: 41550

American (AMR) AF: 0.867 AC: 13264 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.883 AC: 3059 AN: 3464

East Asian (EAS) AF: 0.999 AC: 5173 AN: 5180

South Asian (SAS) AF: 0.944 AC: 4560 AN: 4830

European-Finnish (FIN) AF: 0.726 AC: 7662 AN: 10556

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.755 AC: 51254 AN: 67930

Other (OTH) AF: 0.849 AC: 1795 AN: 2114

Alfa AF: 0.789 Hom.: 110601

Bravo AF: 0.854

TwinsUK AF: 0.752 AC: 2789

ALSPAC AF: 0.754 AC: 2906

ESP6500AA AF: 0.947 AC: 4163

ESP6500EA AF: 0.762 AC: 6544

ExAC AF: 0.835 AC: 100820

Asia WGS AF: 0.972 AC: 3381 AN: 3478

EpiCase AF: 0.775

EpiControl AF: 0.776

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.25
DANN	Benign	0.37
DEOGEN2	Benign	0.065	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.016
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.018
Sift	Benign	0.41	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.24
ClinPred		0.0013	T
GERP RS		-2.8
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3210908; hg19: chr11-406483; COSMIC: COSV58988862; COSMIC: COSV58988862;