chr11-18269755-G-A

Position:

• chr11-18269755-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_199161.5(SAA1):​c.269G>A​(p.Gly90Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000872 in 1,614,026 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0010 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (13 hom.)
• Consequence: SAA1 NM_199161.5 missense
• Clinical Significance: Benign criteria provided, single submitter P:1 B:1
• Conservation: PhyloP100: 1.75

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03837776).
• BP6: Variant 11-18269755-G-A is Benign according to our data. Variant chr11-18269755-G-A is described in ClinVar as [Benign]. Clinvar id is 18107.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00104 (158/152306) while in subpopulation EAS AF= 0.0191 (99/5180). AF 95% confidence interval is 0.0161. There are 2 homozygotes in gnomad4. There are 94 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAA1	NM_199161.5	c.269G>A	p.Gly90Asp	missense_variant	4/4	ENST00000356524.9
SAA1	NM_000331.6	c.269G>A	p.Gly90Asp	missense_variant	4/4
SAA1	NM_001178006.3	c.269G>A	p.Gly90Asp	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAA1	ENST00000356524.9	c.269G>A	p.Gly90Asp	missense_variant	4/4	1	NM_199161.5	P1

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 159 AN: 152188 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0193

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00207 AC: 521 AN: 251378 Hom.: 8 AF XY: 0.00189 AC XY: 257 AN XY: 135874

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.0185

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000855 AC: 1250 AN: 1461720 Hom.: 13 Cov.: 31 AF XY: 0.000868 AC XY: 631 AN XY: 727168

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.0201

Gnomad4 SAS exome AF: 0.00155

Gnomad4 FIN exome AF: 0.000505

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00104 AC: 158 AN: 152306 Hom.: 2 Cov.: 33 AF XY: 0.00126 AC XY: 94 AN XY: 74468

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0191

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000974 Hom.: 2

Bravo AF: 0.00108

ExAC AF: 0.00186 AC: 226

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SERUM AMYLOID A VARIANT Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1992

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T;T;T
Eigen	Benign	0.023
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.89	.;.;D
MetaRNN	Benign	0.038	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	4.6e-9	A;A;A
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Benign	0.15
Sift	Benign	0.049	D;D;D
Sift4G	Benign	0.072	T;T;T
Vest4		0.41
MVP		0.22
MPC		0.033
ClinPred		0.11	T
GERP RS		3.3
gMVP		0.66

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: rs79681911; hg19: chr11-18291302;