NM_199161.5:c.199C>G

Variant names:

• chr11-18269302-C-G
• rs1354927195
• NM_199161.5:c.199C>G

Variant summary

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

The NM_199161.5(SAA1):​c.199C>G​(p.Pro67Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P67S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SAA1 NM_199161.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAA1	NM_199161.5	c.199C>G	p.Pro67Ala	missense_variant	Exon 3 of 4	ENST00000356524.9	NP_954630.2
SAA1	NM_000331.6	c.199C>G	p.Pro67Ala	missense_variant	Exon 3 of 4		NP_000322.3
SAA1	NM_001178006.3	c.199C>G	p.Pro67Ala	missense_variant	Exon 4 of 5		NP_001171477.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAA1	ENST00000356524.9	c.199C>G	p.Pro67Ala	missense_variant	Exon 3 of 4	1	NM_199161.5	ENSP00000348918.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.16e-7 AC: 1 AN: 1396928 Hom.: 0 Cov.: 48 AF XY: 0.00000145 AC XY: 1 AN XY: 688236

African (AFR) AF: 0.00 AC: 0 AN: 31000

American (AMR) AF: 0.00 AC: 0 AN: 33814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23178

East Asian (EAS) AF: 0.00 AC: 0 AN: 38476

South Asian (SAS) AF: 0.00 AC: 0 AN: 76102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5506

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1080256

Other (OTH) AF: 0.00 AC: 0 AN: 57642

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.087	T;T;.;T
Eigen	Benign	0.13
Eigen_PC	Benign	-0.059
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.83	.;.;T;T
M_CAP	Benign	0.0043	T
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Benign	-0.79	T
PhyloP100		2.1
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-6.5	D;D;.;D
REVEL	Benign	0.13
Sift	Benign	0.030	D;D;.;D
Sift4G	Benign	0.065	T;T;.;T
Vest4		0.20
MutPred		0.70		Gain of catalytic residue at P67 (P = 0.0116);Gain of catalytic residue at P67 (P = 0.0116);Gain of catalytic residue at P67 (P = 0.0116);Gain of catalytic residue at P67 (P = 0.0116);
MVP		0.52
MPC		2.9
ClinPred		0.99	D
GERP RS		3.2
gMVP		0.30
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

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Other links and lift over

dbSNP: rs1354927195; hg19: chr11-18290849;