11-18269302-C-T

Position:

• chr11-18269302-C-T

Variant summary

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

The NM_199161.5(SAA1):​c.199C>T​(p.Pro67Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SAA1 NM_199161.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.06

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 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	Protein	UniProt
SAA1	NM_199161.5	c.199C>T	p.Pro67Ser	missense_variant	3/4	ENST00000356524.9	NP_954630.2
SAA1	NM_000331.6	c.199C>T	p.Pro67Ser	missense_variant	3/4		NP_000322.3
SAA1	NM_001178006.3	c.199C>T	p.Pro67Ser	missense_variant	4/5		NP_001171477.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SAA1	ENST00000356524.9	c.199C>T	p.Pro67Ser	missense_variant	3/4	1	NM_199161.5	ENSP00000348918.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000143 AC: 2 AN: 1396928 Hom.: 0 Cov.: 48 AF XY: 0.00000145 AC XY: 1 AN XY: 688236

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: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2023

The c.199C>T (p.P67S) 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 199, causing the proline (P) at amino acid position 67 to be replaced by a serine (S). 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	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	T;T;.;T
Eigen	Uncertain	0.21
Eigen_PC	Benign	-0.0082
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.84	.;.;T;D
M_CAP	Benign	0.0045	T
MetaRNN	Uncertain	0.57	D;D;D;D
MetaSVM	Benign	-0.79	T
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-6.6	D;D;.;D
REVEL	Benign	0.16
Sift	Benign	0.15	T;T;.;T
Sift4G	Benign	0.080	T;T;.;T
Vest4		0.23
MutPred		0.69		Gain of glycosylation at P67 (P = 0.0266);Gain of glycosylation at P67 (P = 0.0266);Gain of glycosylation at P67 (P = 0.0266);Gain of glycosylation at P67 (P = 0.0266);
MVP		0.55
MPC		3.0
ClinPred		0.99	D
GERP RS		3.2
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-18290849;