rs4917

Positions:

• chr3-186619924-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001622.4(AHSG):​c.743T>C​(p.Met248Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 1,611,398 control chromosomes in the GnomAD database, including 358,503 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.68 (35876 hom., cov: 31)
  • Exomes 𝑓: 0.66 (322627 hom.)
• Consequence: AHSG NM_001622.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.433

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9404777E-6).
• BP6: Variant 3-186619924-T-C is Benign according to our data. Variant chr3-186619924-T-C is described in ClinVar as [Benign]. Clinvar id is 16043.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHSG	NM_001622.4	c.743T>C	p.Met248Thr	missense_variant	6/7	ENST00000411641.7
AHSG	NM_001354571.2	c.746T>C	p.Met249Thr	missense_variant	6/7
AHSG	NM_001354572.2	c.740T>C	p.Met247Thr	missense_variant	6/7
AHSG	NM_001354573.2	c.676-662T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHSG	ENST00000411641.7	c.743T>C	p.Met248Thr	missense_variant	6/7	1	NM_001622.4	P3
HRG-AS1	ENST00000630178.2	n.239-39958A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.684 AC: 103930 AN: 151990 Hom.: 35853 Cov.: 31

Gnomad AFR AF: 0.746

Gnomad AMI AF: 0.592

Gnomad AMR AF: 0.626

Gnomad ASJ AF: 0.761

Gnomad EAS AF: 0.736

Gnomad SAS AF: 0.797

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.844

Gnomad NFE AF: 0.655

Gnomad OTH AF: 0.722

GnomAD3 exomes AF: 0.676 AC: 168819 AN: 249888 Hom.: 57878 AF XY: 0.685 AC XY: 92597 AN XY: 135138

Gnomad AFR exome AF: 0.750

Gnomad AMR exome AF: 0.566

Gnomad ASJ exome AF: 0.765

Gnomad EAS exome AF: 0.735

Gnomad SAS exome AF: 0.794

Gnomad FIN exome AF: 0.603

Gnomad NFE exome AF: 0.662

Gnomad OTH exome AF: 0.688

GnomAD4 exome AF: 0.663 AC: 966968 AN: 1459290 Hom.: 322627 Cov.: 38 AF XY: 0.668 AC XY: 484685 AN XY: 726042

Gnomad4 AFR exome AF: 0.748

Gnomad4 AMR exome AF: 0.573

Gnomad4 ASJ exome AF: 0.765

Gnomad4 EAS exome AF: 0.738

Gnomad4 SAS exome AF: 0.789

Gnomad4 FIN exome AF: 0.605

Gnomad4 NFE exome AF: 0.649

Gnomad4 OTH exome AF: 0.687

GnomAD4 genome AF: 0.684 AC: 104002 AN: 152108 Hom.: 35876 Cov.: 31 AF XY: 0.684 AC XY: 50859 AN XY: 74372

Gnomad4 AFR AF: 0.745

Gnomad4 AMR AF: 0.626

Gnomad4 ASJ AF: 0.761

Gnomad4 EAS AF: 0.736

Gnomad4 SAS AF: 0.797

Gnomad4 FIN AF: 0.605

Gnomad4 NFE AF: 0.655

Gnomad4 OTH AF: 0.723

Alfa AF: 0.675 Hom.: 83297

Bravo AF: 0.686

TwinsUK AF: 0.636 AC: 2358

ALSPAC AF: 0.635 AC: 2446

ESP6500AA AF: 0.750 AC: 3303

ESP6500EA AF: 0.652 AC: 5607

ExAC AF: 0.683 AC: 82916

Asia WGS AF: 0.728 AC: 2533 AN: 3478

EpiCase AF: 0.683

EpiControl AF: 0.687

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Alopecia-intellectual disability syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

RECLASSIFIED - ALPHA-2-HS-GLYCOPROTEIN POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jun 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.9
DANN	Benign	0.75
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.10	T;T
MetaRNN	Benign	0.0000019	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	2.4	N;N
REVEL	Benign	0.015
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.038
MPC		0.094
ClinPred		0.0025	T
GERP RS		-0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs4917; hg19: chr3-186337713; COSMIC: COSV56607200; COSMIC: COSV56607200;