rs1136743

Variant names:

• chr11-18269312-C-T
• rs1136743
• NM_199161.5:c.209C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_199161.5(SAA1):​c.209C>T​(p.Ala70Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 148,460 control chromosomes in the GnomAD database, including 18,724 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (18724 hom., cov: 28)
  • Exomes 𝑓: 0.55 (148135 hom.)
  • Failed GnomAD Quality Control
• Consequence: SAA1 NM_199161.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:4
• Conservation: PhyloP100: -0.932
• Publications: 36 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011088252).
• BP6: Variant 11-18269312-C-T is Benign according to our data. Variant chr11-18269312-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 18108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAA1	NM_199161.5	c.209C>T	p.Ala70Val	missense_variant	Exon 3 of 4	ENST00000356524.9	NP_954630.2
SAA1	NM_000331.6	c.209C>T	p.Ala70Val	missense_variant	Exon 3 of 4		NP_000322.3
SAA1	NM_001178006.3	c.209C>T	p.Ala70Val	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.209C>T	p.Ala70Val	missense_variant	Exon 3 of 4	1	NM_199161.5	ENSP00000348918.4

Frequencies

GnomAD3 genomes AF: 0.547 AC: 81134 AN: 148342 Hom.: 18715 Cov.: 28

Gnomad AFR AF: 0.532

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.451

Gnomad FIN AF: 0.593

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.597

Gnomad OTH AF: 0.510

GnomAD2 exomes AF: 0.479 AC: 73276 AN: 152964 AF XY: 0.479

Gnomad AFR exome AF: 0.499

Gnomad AMR exome AF: 0.418

Gnomad ASJ exome AF: 0.366

Gnomad EAS exome AF: 0.250

Gnomad FIN exome AF: 0.552

Gnomad NFE exome AF: 0.543

Gnomad OTH exome AF: 0.489

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.552 AC: 741180 AN: 1343586 Hom.: 148135 Cov.: 42 AF XY: 0.547 AC XY: 360796 AN XY: 659288

African (AFR) AF: 0.501 AC: 14629 AN: 29218

American (AMR) AF: 0.445 AC: 12585 AN: 28292

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 8199 AN: 21404

East Asian (EAS) AF: 0.266 AC: 9950 AN: 37428

South Asian (SAS) AF: 0.432 AC: 30695 AN: 71050

European-Finnish (FIN) AF: 0.584 AC: 28553 AN: 48930

Middle Eastern (MID) AF: 0.348 AC: 1853 AN: 5320

European-Non Finnish (NFE) AF: 0.579 AC: 605706 AN: 1046342

Other (OTH) AF: 0.522 AC: 29010 AN: 55602

GnomAD4 genome AF: 0.547 AC: 81183 AN: 148460 Hom.: 18724 Cov.: 28 AF XY: 0.540 AC XY: 39240 AN XY: 72622

African (AFR) AF: 0.532 AC: 21639 AN: 40682

American (AMR) AF: 0.502 AC: 7504 AN: 14946

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1392 AN: 3410

East Asian (EAS) AF: 0.277 AC: 1414 AN: 5110

South Asian (SAS) AF: 0.453 AC: 2143 AN: 4734

European-Finnish (FIN) AF: 0.593 AC: 6166 AN: 10400

Middle Eastern (MID) AF: 0.361 AC: 104 AN: 288

European-Non Finnish (NFE) AF: 0.597 AC: 39372 AN: 65936

Other (OTH) AF: 0.505 AC: 1041 AN: 2062

Alfa AF: 0.535 Hom.: 3270

ExAC AF: 0.487 AC: 57822

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Sep 30, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 30, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23437051) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

SERUM AMYLOID A VARIANT Pathogenic:1

Jun 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

SAA1-related disorder Benign:1

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.29
DANN	Benign	0.83
DEOGEN2	Benign	0.011	T;T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.35	.;.;T;T
MetaRNN	Benign	0.0011	T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.93
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N;N;.;N
REVEL	Benign	0.011
Sift	Benign	0.74	T;T;.;T
Sift4G	Benign	1.0	T;T;.;T
Vest4		0.013
MPC		1.7
ClinPred		0.0042	T
GERP RS		-0.058
gMVP		0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1136743; hg19: chr11-18290859; COSMIC: COSV62945873; COSMIC: COSV62945873;