1-223223281-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017982.4(SUSD4):c.1412C>A(p.Ala471Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000405 in 1,408,756 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: SUSD4 NM_017982.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

Genes affected

SUSD4 (HGNC:25470): (sushi domain containing 4) Involved in negative regulation of complement activation, alternative pathway and negative regulation of complement activation, classical pathway. Predicted to be located in extracellular region. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37931925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUSD4	NM_017982.4	c.1412C>A	p.Ala471Glu	missense_variant	8/9	ENST00000366878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUSD4	ENST00000366878.9	c.1412C>A	p.Ala471Glu	missense_variant	8/9	1	NM_017982.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000488 AC: 1 AN: 204944 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 109328

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000405 AC: 57 AN: 1408756 Hom.: 0 Cov.: 31 AF XY: 0.0000359 AC XY: 25 AN XY: 695470

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: 0.0000515

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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

Apr 20, 2023

The c.1412C>A (p.A471E) alteration is located in exon 8 (coding exon 7) of the SUSD4 gene. This alteration results from a C to A substitution at nucleotide position 1412, causing the alanine (A) at amino acid position 471 to be replaced by a glutamic acid (E). 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	0.17
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.034	T;T;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.97	L;L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N;N;.;.
REVEL	Benign	0.15
Sift	Uncertain	0.0060	D;D;.;.
Sift4G	Uncertain	0.020	D;D;D;D
Polyphen		0.96	D;D;.;.
Vest4		0.57
MutPred		0.072		Gain of relative solvent accessibility (P = 0.0483);Gain of relative solvent accessibility (P = 0.0483);.;Gain of relative solvent accessibility (P = 0.0483);
MVP		0.29
MPC		0.58
ClinPred		0.76	D
GERP RS		3.9
Varity_R		0.27
gMVP		0.48

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: rs941712116; hg19: chr1-223396623;