rs4831

Variant names:

• chr3-186613180-C-G
• rs4831
• NM_001622.4:c.39C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001622.4(AHSG):​c.39C>G​(p.Leu13Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,613,722 control chromosomes in the GnomAD database, including 21,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.19 (3506 hom., cov: 31)
  • Exomes 𝑓: 0.15 (17803 hom.)
• Consequence: AHSG NM_001622.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.124
• Publications: 19 publications found

Genes affected

AHSG (HGNC:349): (alpha 2-HS glycoprotein) The protein encoded by this gene is a negatively-charged serum glycoprotein that is synthesized by hepatocytes. The encoded protein consists of two polypeptide chains, which are both cleaved from a proprotein encoded from a single mRNA. It is involved in several processes, including endocytosis, brain development, and the formation of bone tissue. Defects in this gene are a cause of susceptibility to leanness. [provided by RefSeq, Aug 2017]

HRG-AS1 (HGNC:55915): (HRG and FETUB antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 3-186613180-C-G is Benign according to our data. Variant chr3-186613180-C-G is described in ClinVar as Benign. ClinVar VariationId is 3058930.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.124 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHSG	NM_001622.4	c.39C>G	p.Leu13Leu	synonymous_variant	Exon 1 of 7	ENST00000411641.7	NP_001613.2
AHSG	NM_001354571.2	c.39C>G	p.Leu13Leu	synonymous_variant	Exon 1 of 7		NP_001341500.1
AHSG	NM_001354572.2	c.39C>G	p.Leu13Leu	synonymous_variant	Exon 1 of 7		NP_001341501.1
AHSG	NM_001354573.2	c.39C>G	p.Leu13Leu	synonymous_variant	Exon 1 of 6		NP_001341502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHSG	ENST00000411641.7	c.39C>G	p.Leu13Leu	synonymous_variant	Exon 1 of 7	1	NM_001622.4	ENSP00000393887.2

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29543 AN: 151920 Hom.: 3500 Cov.: 31

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.0958

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.216

GnomAD2 exomes AF: 0.158 AC: 39644 AN: 251210 AF XY: 0.158

Gnomad AFR exome AF: 0.336

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.241

Gnomad EAS exome AF: 0.113

Gnomad FIN exome AF: 0.0955

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.149 AC: 218115 AN: 1461684 Hom.: 17803 Cov.: 33 AF XY: 0.150 AC XY: 109076 AN XY: 727162

African (AFR) AF: 0.340 AC: 11385 AN: 33472

American (AMR) AF: 0.133 AC: 5940 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 6263 AN: 26134

East Asian (EAS) AF: 0.144 AC: 5704 AN: 39694

South Asian (SAS) AF: 0.208 AC: 17932 AN: 86248

European-Finnish (FIN) AF: 0.0922 AC: 4926 AN: 53412

Middle Eastern (MID) AF: 0.242 AC: 1396 AN: 5768

European-Non Finnish (NFE) AF: 0.139 AC: 154719 AN: 1111848

Other (OTH) AF: 0.163 AC: 9850 AN: 60386

GnomAD4 genome AF: 0.194 AC: 29560 AN: 152038 Hom.: 3506 Cov.: 31 AF XY: 0.191 AC XY: 14177 AN XY: 74334

African (AFR) AF: 0.330 AC: 13679 AN: 41414

American (AMR) AF: 0.174 AC: 2653 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 856 AN: 3470

East Asian (EAS) AF: 0.122 AC: 630 AN: 5166

South Asian (SAS) AF: 0.194 AC: 932 AN: 4816

European-Finnish (FIN) AF: 0.0958 AC: 1014 AN: 10586

Middle Eastern (MID) AF: 0.257 AC: 75 AN: 292

European-Non Finnish (NFE) AF: 0.136 AC: 9213 AN: 67980

Other (OTH) AF: 0.215 AC: 455 AN: 2114

Alfa AF: 0.163 Hom.: 775

Bravo AF: 0.206

Asia WGS AF: 0.167 AC: 580 AN: 3478

EpiCase AF: 0.146

EpiControl AF: 0.157

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

AHSG-related disorder Benign:1

Oct 29, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.9
DANN	Benign	0.72
PhyloP100		0.12
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs4831; hg19: chr3-186330969; COSMIC: COSV56607297;