chr11-18269272-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_199161.5(SAA1):​c.169C>T​(p.Arg57Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000042 in 1,594,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R57Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

SAA1
NM_199161.5 missense

Scores

1
4
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.07
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SAA1NM_199161.5 linkuse as main transcriptc.169C>T p.Arg57Trp missense_variant 3/4 ENST00000356524.9
SAA1NM_000331.6 linkuse as main transcriptc.169C>T p.Arg57Trp missense_variant 3/4
SAA1NM_001178006.3 linkuse as main transcriptc.169C>T p.Arg57Trp missense_variant 4/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SAA1ENST00000356524.9 linkuse as main transcriptc.169C>T p.Arg57Trp missense_variant 3/41 NM_199161.5 P1

Frequencies

GnomAD3 genomes
AF:
0.0000527
AC:
8
AN:
151754
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000657
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000947
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000883
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000696
AC:
16
AN:
229938
Hom.:
0
AF XY:
0.0000882
AC XY:
11
AN XY:
124654
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000318
Gnomad ASJ exome
AF:
0.000106
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000484
Gnomad NFE exome
AF:
0.000127
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000409
AC:
59
AN:
1442282
Hom.:
0
Cov.:
49
AF XY:
0.0000531
AC XY:
38
AN XY:
715010
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000240
Gnomad4 ASJ exome
AF:
0.000117
Gnomad4 EAS exome
AF:
0.0000254
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000454
Gnomad4 OTH exome
AF:
0.0000672
GnomAD4 genome
AF:
0.0000527
AC:
8
AN:
151754
Hom.:
0
Cov.:
30
AF XY:
0.0000405
AC XY:
3
AN XY:
74098
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000657
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000947
Gnomad4 NFE
AF:
0.0000883
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000340
ExAC
AF:
0.0000578
AC:
7

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 12, 2022The c.169C>T (p.R57W) alteration is located in exon 3 (coding exon 2) of the SAA1 gene. This alteration results from a C to T substitution at nucleotide position 169, causing the arginine (R) at amino acid position 57 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.070
T
BayesDel_noAF
Benign
-0.10
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.13
T;T;.;T
Eigen
Benign
0.044
Eigen_PC
Benign
-0.082
FATHMM_MKL
Benign
0.71
D
LIST_S2
Benign
0.85
.;.;D;D
M_CAP
Benign
0.0040
T
MetaRNN
Uncertain
0.56
D;D;D;D
MetaSVM
Benign
-0.90
T
MutationTaster
Benign
0.96
D;D;D
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-6.4
D;D;.;D
REVEL
Benign
0.28
Sift
Benign
0.12
T;T;.;T
Sift4G
Uncertain
0.058
T;T;.;T
Vest4
0.42
MVP
0.15
MPC
2.0
ClinPred
0.72
D
GERP RS
2.3
gMVP
0.69

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs900843725; hg19: chr11-18290819; COSMIC: COSV62946631; COSMIC: COSV62946631; API