chr1-223264738-T-C

Position:

• chr1-223264738-T-C

Variant summary

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

The NM_017982.4(SUSD4):​c.616A>G​(p.Ile206Val) 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: 33)
• Consequence: SUSD4 NM_017982.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10289931).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUSD4	NM_017982.4	c.616A>G	p.Ile206Val	missense_variant	5/9	ENST00000366878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUSD4	ENST00000366878.9	c.616A>G	p.Ile206Val	missense_variant	5/9	1	NM_017982.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Dec 12, 2023

The c.616A>G (p.I206V) alteration is located in exon 5 (coding exon 4) of the SUSD4 gene. This alteration results from a A to G substitution at nucleotide position 616, causing the isoleucine (I) at amino acid position 206 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.8
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T;T;.;.;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.71	.;T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.10	T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-1.0	N;N;.;.;N
MutationTaster	Benign	0.90	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.020	N;N;.;.;N
REVEL	Benign	0.18
Sift	Benign	1.0	T;T;.;.;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0040	B;B;B;.;P
Vest4		0.14
MutPred		0.50		Gain of glycosylation at T204 (P = 0.1563);Gain of glycosylation at T204 (P = 0.1563);.;Gain of glycosylation at T204 (P = 0.1563);Gain of glycosylation at T204 (P = 0.1563);
MVP		0.27
MPC		0.15
ClinPred		0.67	D
GERP RS		5.3
Varity_R		0.026
gMVP		0.20

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: rs1558194141; hg19: chr1-223438080;