Genetic Variant NM_030754.5:c.266G>A (chr11-18245480-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_030754.5(SAA2):c.266G>A(p.Arg89His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.851 in 1,613,990 control chromosomes in the GnomAD database, including 587,906 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.81 ( 50183 hom., cov: 33)

Exomes 𝑓: 0.86 ( 537723 hom. )

Consequence

SAA2
NM_030754.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.93

Publications

36 publications found

Variant links:

Genes affected

SAA2 (HGNC:10514): (serum amyloid A2) 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. [provided by RefSeq, Jul 2020]

SAA2 links:

SAA2-SAA4 (HGNC:39550): (SAA2-SAA4 readthrough) This locus represents naturally occurring read-through transcription between the neighboring serum amyloid A2 and serum amyloid A4 genes on chromosome 11. The read-through transcript produces a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Dec 2010]

SAA2-SAA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.348477E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAA2	NM_030754.5 link	c.266G>A	p.Arg89His	missense_variant	Exon 4 of 4	ENST00000256733.9	NP_110381.2	P0DJI9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAA2	ENST00000256733.9 link	c.266G>A	p.Arg89His	missense_variant	Exon 4 of 4	1	NM_030754.5	ENSP00000256733.5		P0DJI9-1
SAA2-SAA4	ENST00000524555.3 link	c.230+430G>A		intron_variant	Intron 3 of 5	3		ENSP00000485552.1		A0A096LPE2

Frequencies

GnomAD3 genomes

AF:

0.805

AC:

122483

AN:

152070

Hom.:

50148

Cov.:

show subpopulations

Gnomad AFR

AF:

0.655

Gnomad AMI

AF:

0.821

Gnomad AMR

AF:

0.807

Gnomad ASJ

AF:

0.849

Gnomad EAS

AF:

0.933

Gnomad SAS

AF:

0.736

Gnomad FIN

AF:

0.936

Gnomad MID

AF:

0.761

Gnomad NFE

AF:

0.869

Gnomad OTH

AF:

0.801

GnomAD2 exomes

AF:

0.835

AC:

209909

AN:

251272

AF XY:

0.837

show subpopulations

Gnomad AFR exome

AF:

0.655

Gnomad AMR exome

AF:

0.770

Gnomad ASJ exome

AF:

0.839

Gnomad EAS exome

AF:

0.941

Gnomad FIN exome

AF:

0.930

Gnomad NFE exome

AF:

0.871

Gnomad OTH exome

AF:

0.831

GnomAD4 exome

AF:

0.856

AC:

1251130

AN:

1461802

Hom.:

537723

Cov.:

AF XY:

0.854

AC XY:

620790

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.641

AC:

21460

AN:

33472

American (AMR)

AF:

0.772

AC:

34535

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.843

AC:

22025

AN:

26136

East Asian (EAS)

AF:

0.915

AC:

36324

AN:

39700

South Asian (SAS)

AF:

0.747

AC:

64432

AN:

86258

European-Finnish (FIN)

AF:

0.923

AC:

49289

AN:

53418

Middle Eastern (MID)

AF:

0.754

AC:

4348

AN:

5764

European-Non Finnish (NFE)

AF:

0.871

AC:

968346

AN:

1111946

Other (OTH)

AF:

0.834

AC:

50371

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

10030

20060

30091

40121

50151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21250

42500

63750

85000

106250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.805

AC:

122570

AN:

152188

Hom.:

50183

Cov.:

AF XY:

0.809

AC XY:

60219

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.655

AC:

27172

AN:

41470

American (AMR)

AF:

0.806

AC:

12343

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.849

AC:

2948

AN:

3472

East Asian (EAS)

AF:

0.933

AC:

4825

AN:

5170

South Asian (SAS)

AF:

0.738

AC:

3558

AN:

4822

European-Finnish (FIN)

AF:

0.936

AC:

9941

AN:

10620

Middle Eastern (MID)

AF:

0.753

AC:

220

AN:

292

European-Non Finnish (NFE)

AF:

0.869

AC:

59122

AN:

68010

Other (OTH)

AF:

0.801

AC:

1694

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1166

2332

3497

4663

5829

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

872

1744

2616

3488

4360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.849

Hom.:

217558

Bravo

AF:

0.792

TwinsUK

AF:

0.885

AC:

3283

ALSPAC

AF:

0.870

AC:

3352

ESP6500AA

AF:

0.683

AC:

3004

ESP6500EA

AF:

0.860

AC:

7382

ExAC

AF:

0.831

AC:

100920

Asia WGS

AF:

0.766

AC:

2666

AN:

3478

EpiCase

AF:

0.860

EpiControl

AF:

0.863

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.89

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.039

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.056

T;T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.045

.;.;T

MetaRNN

Benign

8.3e-7

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.49

N;N;N

PhyloP100

-3.9

PROVEAN

Benign

-0.10

N;N;N

REVEL

Benign

0.061

Sift

Benign

0.52

T;T;T

Sift4G

Benign

0.34

T;T;T

Vest4

0.0060

MPC

0.021

ClinPred

0.026

GERP RS

-10

Varity_R

0.022

gMVP

0.26

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over