rs12218

Variant names:

• chr11-18269774-T-C
• rs12218
• NM_199161.5:c.288T>C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_199161.5(SAA1):​c.288T>C​(p.Ala96Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 1,613,852 control chromosomes in the GnomAD database, including 195,674 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (12485 hom., cov: 32)
  • Exomes 𝑓: 0.49 (183189 hom.)
• Consequence: SAA1 NM_199161.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP7: Synonymous conserved (PhyloP=-1.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAA1	NM_199161.5	c.288T>C	p.Ala96Ala	synonymous_variant	Exon 4 of 4	ENST00000356524.9	NP_954630.2
SAA1	NM_000331.6	c.288T>C	p.Ala96Ala	synonymous_variant	Exon 4 of 4		NP_000322.3
SAA1	NM_001178006.3	c.288T>C	p.Ala96Ala	synonymous_variant	Exon 5 of 5		NP_001171477.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAA1	ENST00000356524.9	c.288T>C	p.Ala96Ala	synonymous_variant	Exon 4 of 4	1	NM_199161.5	ENSP00000348918.4

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55743 AN: 152040 Hom.: 12486 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.373

GnomAD3 exomes AF: 0.417 AC: 104900 AN: 251420 Hom.: 23428 AF XY: 0.420 AC XY: 57106 AN XY: 135888

Gnomad AFR exome AF: 0.0975

Gnomad AMR exome AF: 0.428

Gnomad ASJ exome AF: 0.313

Gnomad EAS exome AF: 0.301

Gnomad SAS exome AF: 0.371

Gnomad FIN exome AF: 0.446

Gnomad NFE exome AF: 0.494

Gnomad OTH exome AF: 0.432

GnomAD4 exome AF: 0.491 AC: 717446 AN: 1461692 Hom.: 183189 Cov.: 50 AF XY: 0.486 AC XY: 353386 AN XY: 727150

Gnomad4 AFR exome AF: 0.0849

Gnomad4 AMR exome AF: 0.433

Gnomad4 ASJ exome AF: 0.316

Gnomad4 EAS exome AF: 0.309

Gnomad4 SAS exome AF: 0.369

Gnomad4 FIN exome AF: 0.451

Gnomad4 NFE exome AF: 0.531

Gnomad4 OTH exome AF: 0.449

GnomAD4 genome AF: 0.366 AC: 55749 AN: 152160 Hom.: 12485 Cov.: 32 AF XY: 0.364 AC XY: 27056 AN XY: 74386

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.435

Gnomad4 ASJ AF: 0.325

Gnomad4 EAS AF: 0.310

Gnomad4 SAS AF: 0.374

Gnomad4 FIN AF: 0.442

Gnomad4 NFE AF: 0.504

Gnomad4 OTH AF: 0.368

Alfa AF: 0.428 Hom.: 6681

Bravo AF: 0.355

Asia WGS AF: 0.331 AC: 1151 AN: 3478

EpiCase AF: 0.477

EpiControl AF: 0.470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.34
DANN	Benign	0.50

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: rs12218; hg19: chr11-18291321; COSMIC: COSV62946044; COSMIC: COSV62946044;