chr1-159588586-C-T

Variant names:

• chr1-159588586-C-T
• NM_001639.4:c.550C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001639.4(APCS):​c.550C>T​(p.Pro184Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: APCS NM_001639.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.455
• Publications: 0 publications found

Genes affected

APCS (HGNC:584): (amyloid P component, serum) The protein encoded by this gene is a glycoprotein, belonging to the pentraxin family of proteins, which has a characteristic pentameric organization. These family members have considerable sequence homology which is thought to be the result of gene duplication. The binding of the encoded protein to proteins in the pathological amyloid cross-beta fold suggests its possible role as a chaperone. This protein is also thought to control the degradation of chromatin. It has been demonstrated that this protein binds to apoptotic cells at an early stage, which raises the possibility that it is involved in dealing with apoptotic cells in vivo. [provided by RefSeq, Sep 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040687293).
• BP6: Variant 1-159588586-C-T is Benign according to our data. Variant chr1-159588586-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3883460.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001639.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APCS	NM_001639.4	MANE Select	c.550C>T	p.Pro184Ser	missense	Exon 2 of 2	NP_001630.1	P02743

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APCS	ENST00000255040.3	TSL:1 MANE Select	c.550C>T	p.Pro184Ser	missense	Exon 2 of 2	ENSP00000255040.2	P02743

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461834 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0136242), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.047
DANN	Benign	0.11
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0077	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.6	N
PhyloP100		-0.46
PrimateAI	Benign	0.24	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.067
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.058
MutPred		0.50		Loss of catalytic residue at P184 (P = 0.0053)
MVP		0.31
MPC		0.050
ClinPred		0.081	T
GERP RS		0.34
Varity_R		0.066
gMVP		0.56
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr1-159558376;