11-406351-A-T

Variant summary

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

The NM_001135054.2(SIGIRR):c.1067T>A(p.Leu356Gln) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: SIGIRR NM_001135054.2 missense, splice_region
• Scores: Splicing: ADA: 0.3978
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.26

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.1067T>A	p.Leu356Gln	missense_variant, splice_region_variant	9/10	ENST00000431843.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGIRR	ENST00000431843.7	c.1067T>A	p.Leu356Gln	missense_variant, splice_region_variant	9/10	1	NM_001135054.2	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 87

GnomAD4 genome Cov.: 34

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

Jul 26, 2021

The c.1067T>A (p.L356Q) alteration is located in exon 9 (coding exon 8) of the SIGIRR gene. This alteration results from a T to A substitution at nucleotide position 1067, causing the leucine (L) at amino acid position 356 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	0.19
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.44	T;.;.;T;T
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.44	T;D;D;D;T
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;D;D;D;D
Vest4		0.74, 0.74, 0.73, 0.67
MutPred		0.40		.;Gain of solvent accessibility (P = 0.0044);Gain of solvent accessibility (P = 0.0044);Gain of solvent accessibility (P = 0.0044);Gain of solvent accessibility (P = 0.0044);
MVP		0.61
MPC		0.86
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.68
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.40
dbscSNV1_RF	Benign	0.58
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: chr11-406351;