rs4917

Variant names:

• chr3-186619924-T-C
• rs4917
• NM_001622.4:c.743T>C

Your query was ambiguous. Multiple possible variants found:

• chr3-186619924-T-C
• chr3-186619924-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 14/20 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, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.433
• Publications: 91 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 -20 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 VariationId is 16043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001622.4. 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
	AHSG	NM_001622.4	MANE Select	c.743T>C	p.Met248Thr	missense	Exon 6 of 7	NP_001613.2	P02765
	AHSG	NM_001354571.2		c.746T>C	p.Met249Thr	missense	Exon 6 of 7	NP_001341500.1	C9JV77
	AHSG	NM_001354572.2		c.740T>C	p.Met247Thr	missense	Exon 6 of 7	NP_001341501.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHSG	ENST00000411641.7	TSL:1 MANE Select	c.743T>C	p.Met248Thr	missense	Exon 6 of 7	ENSP00000393887.2	P02765
	AHSG	ENST00000864095.1		c.782T>C	p.Met261Thr	missense	Exon 6 of 7	ENSP00000534154.1
	AHSG	ENST00000864081.1		c.767T>C	p.Met256Thr	missense	Exon 6 of 7	ENSP00000534140.1

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

GnomAD2 exomes AF: 0.676 AC: 168819 AN: 249888 AF XY: 0.685

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 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

African (AFR) AF: 0.748 AC: 24960 AN: 33350

American (AMR) AF: 0.573 AC: 25315 AN: 44216

Ashkenazi Jewish (ASJ) AF: 0.765 AC: 19957 AN: 26094

East Asian (EAS) AF: 0.738 AC: 29262 AN: 39670

South Asian (SAS) AF: 0.789 AC: 67801 AN: 85972

European-Finnish (FIN) AF: 0.605 AC: 32296 AN: 53348

Middle Eastern (MID) AF: 0.839 AC: 4830 AN: 5760

European-Non Finnish (NFE) AF: 0.649 AC: 721140 AN: 1110590

Other (OTH) AF: 0.687 AC: 41407 AN: 60290

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

African (AFR) AF: 0.745 AC: 30912 AN: 41476

American (AMR) AF: 0.626 AC: 9570 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.761 AC: 2642 AN: 3470

East Asian (EAS) AF: 0.736 AC: 3811 AN: 5180

South Asian (SAS) AF: 0.797 AC: 3838 AN: 4818

European-Finnish (FIN) AF: 0.605 AC: 6405 AN: 10586

Middle Eastern (MID) AF: 0.849 AC: 248 AN: 292

European-Non Finnish (NFE) AF: 0.655 AC: 44513 AN: 67984

Other (OTH) AF: 0.723 AC: 1524 AN: 2108

Alfa AF: 0.674 Hom.: 152247

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Alopecia-intellectual disability syndrome 1 (1)
-	-	1	not provided (1)
-	-	1	RECLASSIFIED - AHSG POLYMORPHISM (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.0000019	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.43
PrimateAI	Benign	0.39	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.015
Sift	Benign	1.0	T
Sift4G	Benign	1.0	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
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: rs4917; hg19: chr3-186337713; COSMIC: COSV56607200; COSMIC: COSV56607200;