11-18269312-C-T

Position:

• chr11-18269312-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/17 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:3
• Conservation: PhyloP100: -0.932

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 -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 [Likely_benign]. Clinvar id 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/exons	MANE	UniProt
SAA1	NM_199161.5	c.209C>T	p.Ala70Val	missense_variant	3/4	ENST00000356524.9
SAA1	NM_000331.6	c.209C>T	p.Ala70Val	missense_variant	3/4
SAA1	NM_001178006.3	c.209C>T	p.Ala70Val	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAA1	ENST00000356524.9	c.209C>T	p.Ala70Val	missense_variant	3/4	1	NM_199161.5	P1

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

GnomAD3 exomes AF: 0.479 AC: 73276 AN: 152964 Hom.: 12525 AF XY: 0.479 AC XY: 38711 AN XY: 80854

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 SAS exome AF: 0.410

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

Gnomad4 AFR exome AF: 0.501

Gnomad4 AMR exome AF: 0.445

Gnomad4 ASJ exome AF: 0.383

Gnomad4 EAS exome AF: 0.266

Gnomad4 SAS exome AF: 0.432

Gnomad4 FIN exome AF: 0.584

Gnomad4 NFE exome AF: 0.579

Gnomad4 OTH exome AF: 0.522

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

Gnomad4 AFR AF: 0.532

Gnomad4 AMR AF: 0.502

Gnomad4 ASJ AF: 0.408

Gnomad4 EAS AF: 0.277

Gnomad4 SAS AF: 0.453

Gnomad4 FIN AF: 0.593

Gnomad4 NFE AF: 0.597

Gnomad4 OTH AF: 0.505

Alfa AF: 0.535 Hom.: 3270

ExAC AF: 0.487 AC: 57822

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2020	This variant is associated with the following publications: (PMID: 23437051) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 30, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

SERUM AMYLOID A VARIANT Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
MutationTaster	Benign	1.0	P;P;P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1136743; hg19: chr11-18290859; COSMIC: COSV62945873; COSMIC: COSV62945873;