NM_199161.5:c.216T>C

Variant names:

• chr11-18269319-T-C
• rs1136745
• NM_199161.5:c.216T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_199161.5(SAA1):​c.216T>C​(p.Ala72Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0742 in 119,316 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (189 hom., cov: 29)
  • Exomes 𝑓: 0.16 (204 hom.)
  • Failed GnomAD Quality Control
• Consequence: SAA1 NM_199161.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.185
• Publications: 9 publications found

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

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-18269319-T-C is Benign according to our data. Variant chr11-18269319-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 768434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.185 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 189 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199161.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAA1	NM_199161.5	MANE Select	c.216T>C	p.Ala72Ala	synonymous	Exon 3 of 4	NP_954630.2	P0DJI8
	SAA1	NM_000331.6		c.216T>C	p.Ala72Ala	synonymous	Exon 3 of 4	NP_000322.3
	SAA1	NM_001178006.3		c.216T>C	p.Ala72Ala	synonymous	Exon 4 of 5	NP_001171477.2	P0DJI8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAA1	ENST00000356524.9	TSL:1 MANE Select	c.216T>C	p.Ala72Ala	synonymous	Exon 3 of 4	ENSP00000348918.4	P0DJI8
	SAA1	ENST00000532858.5	TSL:1	c.216T>C	p.Ala72Ala	synonymous	Exon 4 of 5	ENSP00000436866.1	P0DJI8
	SAA1	ENST00000405158.2	TSL:5	c.216T>C	p.Ala72Ala	synonymous	Exon 3 of 4	ENSP00000384906.2	P0DJI8

Frequencies

GnomAD3 genomes AF: 0.0742 AC: 8841 AN: 119220 Hom.: 186 Cov.: 29

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.0917

Gnomad AMR AF: 0.0821

Gnomad ASJ AF: 0.0486

Gnomad EAS AF: 0.0601

Gnomad SAS AF: 0.0195

Gnomad FIN AF: 0.0320

Gnomad MID AF: 0.0508

Gnomad NFE AF: 0.0471

Gnomad OTH AF: 0.0711

GnomAD2 exomes AF: 0.172 AC: 18988 AN: 110122 AF XY: 0.171

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.229

Gnomad FIN exome AF: 0.135

Gnomad NFE exome AF: 0.171

Gnomad OTH exome AF: 0.165

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.155 AC: 167361 AN: 1079154 Hom.: 204 Cov.: 40 AF XY: 0.152 AC XY: 80584 AN XY: 528584

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.168 AC: 4376 AN: 26000

American (AMR) AF: 0.159 AC: 3267 AN: 20514

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 2245 AN: 15546

East Asian (EAS) AF: 0.146 AC: 3555 AN: 24330

South Asian (SAS) AF: 0.0873 AC: 5148 AN: 58978

European-Finnish (FIN) AF: 0.0545 AC: 2142 AN: 39268

Middle Eastern (MID) AF: 0.133 AC: 550 AN: 4126

European-Non Finnish (NFE) AF: 0.165 AC: 139827 AN: 846734

Other (OTH) AF: 0.143 AC: 6251 AN: 43658

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0742 AC: 8855 AN: 119316 Hom.: 189 Cov.: 29 AF XY: 0.0727 AC XY: 4270 AN XY: 58740

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.130 AC: 4657 AN: 35880

American (AMR) AF: 0.0820 AC: 935 AN: 11408

Ashkenazi Jewish (ASJ) AF: 0.0486 AC: 123 AN: 2532

East Asian (EAS) AF: 0.0606 AC: 221 AN: 3646

South Asian (SAS) AF: 0.0198 AC: 80 AN: 4046

European-Finnish (FIN) AF: 0.0320 AC: 286 AN: 8950

Middle Eastern (MID) AF: 0.0500 AC: 11 AN: 220

European-Non Finnish (NFE) AF: 0.0471 AC: 2372 AN: 50396

Other (OTH) AF: 0.0702 AC: 115 AN: 1638

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0997 Hom.: 47

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.0
DANN	Benign	0.30
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1136745; hg19: chr11-18290866; COSMIC: COSV62945917; COSMIC: COSV62945917;