rs900843725

Variant names:

• chr11-18269272-C-T
• rs900843725
• NM_199161.5:c.169C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_199161.5(SAA1):​c.169C>T​(p.Arg57Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000042 in 1,594,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R57Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: SAA1 NM_199161.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07
• Publications: 0 publications found

Genes affected

SAA1 (HGNC:10513): (serum amyloid A1) This gene encodes a member of the serum amyloid A family of apolipoproteins. The encoded preproprotein is proteolytically processed to generate the mature protein. This protein is a major acute phase protein that is highly expressed in response to inflammation and tissue injury. This protein also plays an important role in HDL metabolism and cholesterol homeostasis. High levels of this protein are associated with chronic inflammatory diseases including atherosclerosis, rheumatoid arthritis, Alzheimer's disease and Crohn's disease. This protein may also be a potential biomarker for certain tumors. Finally, antimicrobial activity against S. aureus and E. coli resides in the N-terminal portion of the mature protein. Alternate splicing results in multiple transcript variants that encode the same protein. A pseudogene of this gene is found on chromosome 11. [provided by RefSeq, Jul 2020]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199161.5. 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
	SAA1	NM_199161.5	MANE Select	c.169C>T	p.Arg57Trp	missense	Exon 3 of 4	NP_954630.2	P0DJI8
	SAA1	NM_000331.6		c.169C>T	p.Arg57Trp	missense	Exon 3 of 4	NP_000322.3
	SAA1	NM_001178006.3		c.169C>T	p.Arg57Trp	missense	Exon 4 of 5	NP_001171477.2	P0DJI8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAA1	ENST00000356524.9	TSL:1 MANE Select	c.169C>T	p.Arg57Trp	missense	Exon 3 of 4	ENSP00000348918.4	P0DJI8
	SAA1	ENST00000532858.5	TSL:1	c.169C>T	p.Arg57Trp	missense	Exon 4 of 5	ENSP00000436866.1	P0DJI8
	SAA1	ENST00000405158.2	TSL:5	c.169C>T	p.Arg57Trp	missense	Exon 3 of 4	ENSP00000384906.2	P0DJI8

Frequencies

GnomAD3 genomes AF: 0.0000527 AC: 8 AN: 151754 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000947

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000696 AC: 16 AN: 229938 AF XY: 0.0000882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000318

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000484

Gnomad NFE exome AF: 0.000127

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000409 AC: 59 AN: 1442282 Hom.: 0 Cov.: 49 AF XY: 0.0000531 AC XY: 38 AN XY: 715010

African (AFR) AF: 0.00 AC: 0 AN: 32822

American (AMR) AF: 0.0000240 AC: 1 AN: 41660

Ashkenazi Jewish (ASJ) AF: 0.000117 AC: 3 AN: 25670

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39352

South Asian (SAS) AF: 0.00 AC: 0 AN: 84378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.0000454 AC: 50 AN: 1100416

Other (OTH) AF: 0.0000672 AC: 4 AN: 59556

GnomAD4 genome AF: 0.0000527 AC: 8 AN: 151754 Hom.: 0 Cov.: 30 AF XY: 0.0000405 AC XY: 3 AN XY: 74098

African (AFR) AF: 0.00 AC: 0 AN: 41256

American (AMR) AF: 0.0000657 AC: 1 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.0000947 AC: 1 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67956

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000578 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.20
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.044
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0040	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.90	T
PhyloP100		1.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Benign	0.28
Sift	Benign	0.12	T
Sift4G	Uncertain	0.058	T
Vest4		0.42
MVP		0.15
MPC		2.0
ClinPred		0.72	D
GERP RS		2.3
gMVP		0.69
Mutation Taster		=57/43	polymorphism

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

Other links and lift over

dbSNP: rs900843725; hg19: chr11-18290819; COSMIC: COSV62946631; COSMIC: COSV62946631;