rs1059559

chr11-18269742-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_199161.5(SAA1):c.256T>C(p.Phe86Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000239 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: SAA1 NM_199161.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.88

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0037888587).
• BP6: Variant 11-18269742-T-C is Benign according to our data. Variant chr11-18269742-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 717982.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAA1	NM_199161.5	c.256T>C	p.Phe86Leu	missense_variant	4/4	ENST00000356524.9
SAA1	NM_000331.6	c.256T>C	p.Phe86Leu	missense_variant	4/4
SAA1	NM_001178006.3	c.256T>C	p.Phe86Leu	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAA1	ENST00000356524.9	c.256T>C	p.Phe86Leu	missense_variant	4/4	1	NM_199161.5	P1

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 159 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000386 AC: 97 AN: 251264 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135816

Gnomad AFR exome AF: 0.00449

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000155 AC: 226 AN: 1461686 Hom.: 0 Cov.: 31 AF XY: 0.000157 AC XY: 114 AN XY: 727160

Gnomad4 AFR exome AF: 0.00424

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.00105 AC: 160 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.00109 AC XY: 81 AN XY: 74492

Gnomad4 AFR AF: 0.00339

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000159 Hom.: 0

ExAC AF: 0.000494 AC: 60

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Apr 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.0010
Dann	Benign	0.21
DEOGEN2	Benign	0.0041	T;T;T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.020	N
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.0038	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.050	N;N;N
REVEL	Benign	0.022
Sift	Benign	0.85	T;T;T
Sift4G	Benign	0.85	T;T;T
Vest4		0.043
MutPred		0.40		Gain of disorder (P = 0.2156);Gain of disorder (P = 0.2156);Gain of disorder (P = 0.2156);
MVP		0.014
MPC		0.0077
ClinPred		0.0058	T
GERP RS		-5.2
gMVP		0.24

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: rs1059559; hg19: chr11-18291289;