11-407143-A-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.647T>C(p.Val216Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000148 in 1,348,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: SIGIRR NM_001135054.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.88

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=0.21139231).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGIRR	NM_001135054.2	c.647T>C	p.Val216Ala	missense_variant	7/10	ENST00000431843.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGIRR	ENST00000431843.7	c.647T>C	p.Val216Ala	missense_variant	7/10	1	NM_001135054.2	P1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000148 AC: 2 AN: 1348798 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 668170

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: 0.00000189

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

Bravo AF: 0.00000378

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

Feb 28, 2024

The c.647T>C (p.V216A) alteration is located in exon 7 (coding exon 6) of the SIGIRR gene. This alteration results from a T to C substitution at nucleotide position 647, causing the valine (V) at amino acid position 216 to be replaced by an alanine (A). 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	0.64
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Uncertain	23
Dann	Benign	0.76
DEOGEN2	Benign	0.045	T;T;T;T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.70	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.81	N;N;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.3	N;N;N;N;N
REVEL	Benign	0.075
Sift	Benign	0.53	T;T;T;T;T
Sift4G	Benign	0.45	T;T;T;T;D
Polyphen		0.033	B;B;B;P;.
Vest4		0.29
MutPred		0.37		Gain of disorder (P = 0.0382);Gain of disorder (P = 0.0382);Gain of disorder (P = 0.0382);Gain of disorder (P = 0.0382);.;
MVP		0.35
MPC		0.49
ClinPred		0.63	D
GERP RS		2.9
Varity_R		0.24
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs1220618823; hg19: chr11-407143;