11-18269327-T-C

Position:

• chr11-18269327-T-C

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.224T>C​(p.Val75Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 147,752 control chromosomes in the GnomAD database, including 23,233 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (23233 hom., cov: 28)
  • Exomes 𝑓: 0.60 (180767 hom.)
  • Failed GnomAD Quality Control
• Consequence: SAA1 NM_199161.5 missense
• Scores: Splicing: ADA: 0.00008927
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.68

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=0.0050112307).
• BP6: Variant 11-18269327-T-C is Benign according to our data. Variant chr11-18269327-T-C is described in ClinVar as [Benign]. Clinvar id is 1258441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAA1	NM_199161.5	c.224T>C	p.Val75Ala	missense_variant	3/4	ENST00000356524.9
SAA1	NM_000331.6	c.224T>C	p.Val75Ala	missense_variant	3/4
SAA1	NM_001178006.3	c.224T>C	p.Val75Ala	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAA1	ENST00000356524.9	c.224T>C	p.Val75Ala	missense_variant	3/4	1	NM_199161.5	P1

Frequencies

GnomAD3 genomes AF: 0.601 AC: 88766 AN: 147632 Hom.: 23206 Cov.: 28

Gnomad AFR AF: 0.568

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.557

Gnomad SAS AF: 0.576

Gnomad FIN AF: 0.703

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.557

GnomAD3 exomes AF: 0.534 AC: 63227 AN: 118470 Hom.: 11715 AF XY: 0.532 AC XY: 32497 AN XY: 61134

Gnomad AFR exome AF: 0.517

Gnomad AMR exome AF: 0.474

Gnomad ASJ exome AF: 0.405

Gnomad EAS exome AF: 0.486

Gnomad SAS exome AF: 0.500

Gnomad FIN exome AF: 0.611

Gnomad NFE exome AF: 0.559

Gnomad OTH exome AF: 0.530

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.601 AC: 781752 AN: 1300906 Hom.: 180767 Cov.: 37 AF XY: 0.598 AC XY: 379637 AN XY: 635044

Gnomad4 AFR exome AF: 0.535

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.428

Gnomad4 EAS exome AF: 0.533

Gnomad4 SAS exome AF: 0.532

Gnomad4 FIN exome AF: 0.682

Gnomad4 NFE exome AF: 0.614

Gnomad4 OTH exome AF: 0.576

GnomAD4 genome AF: 0.601 AC: 88846 AN: 147752 Hom.: 23233 Cov.: 28 AF XY: 0.601 AC XY: 43410 AN XY: 72224

Gnomad4 AFR AF: 0.568

Gnomad4 AMR AF: 0.542

Gnomad4 ASJ AF: 0.461

Gnomad4 EAS AF: 0.557

Gnomad4 SAS AF: 0.576

Gnomad4 FIN AF: 0.703

Gnomad4 NFE AF: 0.636

Gnomad4 OTH AF: 0.557

Alfa AF: 0.634 Hom.: 3289

ExAC AF: 0.551 AC: 63027

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2020	This variant is associated with the following publications: (PMID: 23437051) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Benign	0.70
DEOGEN2	Benign	0.079	T;T;.;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.39	.;.;T;T
MetaRNN	Benign	0.0050	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.5	D;D;.;D
REVEL	Benign	0.17
Sift	Benign	0.034	D;D;.;D
Sift4G	Uncertain	0.019	D;D;.;D
Vest4		0.077
MPC		2.5
ClinPred		0.060	T
GERP RS		-3.1
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000089
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.040		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: rs1136747; hg19: chr11-18290874; COSMIC: COSV62945890; COSMIC: COSV62945890;