11-405994-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001135054.2(SIGIRR):c.1135G>C(p.Glu379Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIGIRR NM_001135054.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.56

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17835581).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGIRR	NM_001135054.2	c.1135G>C	p.Glu379Gln	missense_variant	10/10	ENST00000431843.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGIRR	ENST00000431843.7	c.1135G>C	p.Glu379Gln	missense_variant	10/10	1	NM_001135054.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Dec 03, 2021

The c.1135G>C (p.E379Q) alteration is located in exon 10 (coding exon 9) of the SIGIRR gene. This alteration results from a G to C substitution at nucleotide position 1135, causing the glutamic acid (E) at amino acid position 379 to be replaced by a glutamine (Q). 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	0.093
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	23
Dann	Benign	0.92
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.73	T;.;.;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	D;N;N;N
REVEL	Benign	0.065
Sift	Uncertain	0.018	D;D;D;D
Sift4G	Uncertain	0.025	D;D;D;D
Polyphen		0.86	.;P;P;P
Vest4		0.12
MutPred		0.19		.;Loss of catalytic residue at E379 (P = 0.0419);Loss of catalytic residue at E379 (P = 0.0419);Loss of catalytic residue at E379 (P = 0.0419);
MVP		0.45
MPC		0.32
ClinPred		0.76	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.22

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-405994;