11-407131-C-A

Variant summary

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

The NM_001135054.2(SIGIRR):c.659G>T(p.Arg220Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIGIRR NM_001135054.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.74

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGIRR	NM_001135054.2	c.659G>T	p.Arg220Leu	missense_variant	7/10	ENST00000431843.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGIRR	ENST00000431843.7	c.659G>T	p.Arg220Leu	missense_variant	7/10	1	NM_001135054.2	P1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1394344 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 691790

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

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

Mar 03, 2022

The c.659G>T (p.R220L) alteration is located in exon 7 (coding exon 6) of the SIGIRR gene. This alteration results from a G to T substitution at nucleotide position 659, causing the arginine (R) at amino acid position 220 to be replaced by a leucine (L). 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	Pathogenic	0.63
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;T;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Uncertain	0.64	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-4.7	D;D;D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0040	D;D;D;T;D
Sift4G	Benign	0.20	T;T;T;T;D
Polyphen		0.99	D;D;D;D;.
Vest4		0.71
MutPred		0.61		Loss of MoRF binding (P = 0.0396);Loss of MoRF binding (P = 0.0396);Loss of MoRF binding (P = 0.0396);Loss of MoRF binding (P = 0.0396);.;
MVP		0.67
MPC		0.94
ClinPred		1.0	D
GERP RS		2.5
Varity_R		0.70
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr11-407131;