11-18269273-G-A

Variant names:

• chr11-18269273-G-A
• rs748089864
• NM_199161.5:c.170G>A

Variant summary

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

The NM_199161.5(SAA1):​c.170G>A​(p.Arg57Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,593,572 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. R57W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SAA1 NM_199161.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92

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.170G>A	p.Arg57Gln	missense_variant	Exon 3 of 4	ENST00000356524.9	NP_954630.2
SAA1	NM_000331.6	c.170G>A	p.Arg57Gln	missense_variant	Exon 3 of 4		NP_000322.3
SAA1	NM_001178006.3	c.170G>A	p.Arg57Gln	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.170G>A	p.Arg57Gln	missense_variant	Exon 3 of 4	1	NM_199161.5	ENSP00000348918.4

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151806 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000727

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: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.0000131 AC: 3 AN: 229470 AF XY: 0.00000804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000485

Gnomad NFE exome AF: 0.00000977

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000118 AC: 17 AN: 1441648 Hom.: 0 Cov.: 49 AF XY: 0.0000112 AC XY: 8 AN XY: 714648

Gnomad4 AFR exome AF: 0.0000610 AC: 2 AN: 32798

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 41544

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25658

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39328

Gnomad4 SAS exome AF: 0.0000237 AC: 2 AN: 84324

Gnomad4 FIN exome AF: 0.0000190 AC: 1 AN: 52704

Gnomad4 NFE exome AF: 0.00000455 AC: 5 AN: 1100100

Gnomad4 Remaining exome AF: 0.000118 AC: 7 AN: 59496

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151924 Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2 AN XY: 74258

Gnomad4 AFR AF: 0.0000724 AC: 0.0000724393 AN: 0.0000724393

Gnomad4 AMR AF: 0.0000656 AC: 0.0000655996 AN: 0.0000655996

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.000476 AC: 0.00047619 AN: 0.00047619

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.170G>A (p.R57Q) alteration is located in exon 3 (coding exon 2) of the SAA1 gene. This alteration results from a G to A substitution at nucleotide position 170, causing the arginine (R) at amino acid position 57 to be replaced by a glutamine (Q). 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
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.082	T;T;.;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.79	.;.;T;D
M_CAP	Benign	0.0047	T
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Benign	-0.87	T
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.5	D;D;.;D
REVEL	Benign	0.21
Sift	Benign	0.087	T;T;.;T
Sift4G	Uncertain	0.037	D;D;.;D
Vest4		0.34
MVP		0.35
MPC		3.1
ClinPred		0.97	D
GERP RS		3.0
gMVP		0.58
Mutation Taster		=56/44	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

Publications

LitVar

Other links and lift over

dbSNP: rs748089864; hg19: chr11-18290820;