Genetic Variant NM_199161.5:c.182A>C (chr11-18269285-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_199161.5(SAA1):c.182A>C(p.Asp61Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000181 in 1,433,914 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000018 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SAA1
NM_199161.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.41

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]

SAA1 links:

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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 rank	MANE	Protein	UniProt
SAA1	NM_199161.5 link	c.182A>C	p.Asp61Ala	missense_variant	Exon 3 of 4	ENST00000356524.9	NP_954630.2	P0DJI8
SAA1	NM_000331.6 link	c.182A>C	p.Asp61Ala	missense_variant	Exon 3 of 4		NP_000322.3	P0DJI8
SAA1	NM_001178006.3 link	c.182A>C	p.Asp61Ala	missense_variant	Exon 4 of 5		NP_001171477.2	P0DJI8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAA1	ENST00000356524.9 link	c.182A>C	p.Asp61Ala	missense_variant	Exon 3 of 4	1	NM_199161.5	ENSP00000348918.4		P0DJI8

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151782

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000453

AC:

AN:

220702

Hom.:

AF XY:

0.00000836

AC XY:

AN XY:

119556

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000102

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000181

AC:

AN:

1433914

Hom.:

Cov.:

AF XY:

0.0000127

AC XY:

AN XY:

710188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000237

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000132

AC:

AN:

151782

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74114

show subpopulations

Gnomad4 AFR

AF:

0.0000485

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;T;.;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.83

.;.;T;D

M_CAP

Benign

0.0055

MetaRNN

Uncertain

0.53

D;D;D;D

MetaSVM

Benign

-0.83

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-7.1

D;D;.;D

REVEL

Benign

0.17

Sift

Uncertain

0.0020

D;D;.;D

Sift4G

Uncertain

0.0040

D;D;.;D

Vest4

0.54

MVP

0.39

MPC

3.4

ClinPred

0.99

GERP RS

3.2

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over