20-1557629-G-T

Variant summary

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

The NM_178460.3(SIRPD):c.25C>A(p.His9Asn) 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. 15/21 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: SIRPD NM_178460.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.752

Genes affected

SIRPD (HGNC:16248): (signal regulatory protein delta) Predicted to be located in extracellular region. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

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=0.11172241).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRPD	NM_178460.3	c.25C>A	p.His9Asn	missense_variant	1/4	ENST00000381623.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRPD	ENST00000381623.4	c.25C>A	p.His9Asn	missense_variant	1/4	1	NM_178460.3	A2
	ENST00000453770.1	n.25C>A		non_coding_transcript_exon_variant	1/6
SIRPD	ENST00000381621.5	c.25C>A	p.His9Asn	missense_variant	1/4	3		P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Jan 24, 2023

The c.25C>A (p.H9N) alteration is located in exon 1 (coding exon 1) of the SIRPD gene. This alteration results from a C to A substitution at nucleotide position 25, causing the histidine (H) at amino acid position 9 to be replaced by an asparagine (N). 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	0.12
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	0.23
Dann	Benign	0.80
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.00079	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.033
Sift	Benign	0.13	T;T
Sift4G	Uncertain	0.027	D;D
Polyphen		0.28	.;B
Vest4		0.15
MutPred		0.34		Gain of catalytic residue at H9 (P = 0.0059);Gain of catalytic residue at H9 (P = 0.0059);
MVP		0.24
MPC		0.043
ClinPred		0.067	T
GERP RS		-1.7
Varity_R		0.056
gMVP		0.12

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

LitVar

Other links and lift over

dbSNP: rs1382858157; hg19: chr20-1538275;