NM_001622.4:c.767G>C

Variant names:

• chr3-186620593-G-C
• rs4918
• NM_001622.4:c.767G>C

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.767G>C​(p.Ser256Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.66 in 1,592,390 control chromosomes in the GnomAD database, including 349,526 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 0.66 (33428 hom., cov: 31)
  • Exomes 𝑓: 0.66 (316098 hom.)
• Consequence: AHSG NM_001622.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.591
• Publications: 87 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=1.4840803E-6).
• BP6: Variant 3-186620593-G-C is Benign according to our data. Variant chr3-186620593-G-C is described in ClinVar as Benign. ClinVar VariationId is 16044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.775 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.767G>C	p.Ser256Thr	missense	Exon 7 of 7	NP_001613.2	P02765
	AHSG	NM_001354571.2		c.770G>C	p.Ser257Thr	missense	Exon 7 of 7	NP_001341500.1	C9JV77
	AHSG	NM_001354572.2		c.764G>C	p.Ser255Thr	missense	Exon 7 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.767G>C	p.Ser256Thr	missense	Exon 7 of 7	ENSP00000393887.2	P02765
	AHSG	ENST00000864095.1		c.806G>C	p.Ser269Thr	missense	Exon 7 of 7	ENSP00000534154.1
	AHSG	ENST00000864081.1		c.791G>C	p.Ser264Thr	missense	Exon 7 of 7	ENSP00000534140.1

Frequencies

GnomAD3 genomes AF: 0.661 AC: 100416 AN: 151850 Hom.: 33408 Cov.: 31

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.592

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.761

Gnomad EAS AF: 0.735

Gnomad SAS AF: 0.796

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.654

Gnomad OTH AF: 0.704

GnomAD2 exomes AF: 0.670 AC: 165931 AN: 247658 AF XY: 0.681

Gnomad AFR exome AF: 0.671

Gnomad AMR exome AF: 0.563

Gnomad ASJ exome AF: 0.766

Gnomad EAS exome AF: 0.736

Gnomad FIN exome AF: 0.604

Gnomad NFE exome AF: 0.662

Gnomad OTH exome AF: 0.684

GnomAD4 exome AF: 0.660 AC: 951063 AN: 1440422 Hom.: 316098 Cov.: 44 AF XY: 0.665 AC XY: 473939 AN XY: 712262

African (AFR) AF: 0.671 AC: 22209 AN: 33120

American (AMR) AF: 0.568 AC: 24956 AN: 43966

Ashkenazi Jewish (ASJ) AF: 0.765 AC: 19593 AN: 25624

East Asian (EAS) AF: 0.738 AC: 28880 AN: 39152

South Asian (SAS) AF: 0.788 AC: 67479 AN: 85586

European-Finnish (FIN) AF: 0.605 AC: 32148 AN: 53108

Middle Eastern (MID) AF: 0.837 AC: 4775 AN: 5708

European-Non Finnish (NFE) AF: 0.649 AC: 710584 AN: 1094832

Other (OTH) AF: 0.682 AC: 40439 AN: 59326

GnomAD4 genome AF: 0.661 AC: 100482 AN: 151968 Hom.: 33428 Cov.: 31 AF XY: 0.662 AC XY: 49145 AN XY: 74266

African (AFR) AF: 0.668 AC: 27679 AN: 41426

American (AMR) AF: 0.616 AC: 9409 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.761 AC: 2641 AN: 3470

East Asian (EAS) AF: 0.735 AC: 3783 AN: 5148

South Asian (SAS) AF: 0.796 AC: 3838 AN: 4820

European-Finnish (FIN) AF: 0.605 AC: 6384 AN: 10552

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.654 AC: 44477 AN: 67956

Other (OTH) AF: 0.705 AC: 1487 AN: 2110

Alfa AF: 0.669 Hom.: 25743

Bravo AF: 0.661

TwinsUK AF: 0.636 AC: 2360

ALSPAC AF: 0.635 AC: 2447

ESP6500AA AF: 0.669 AC: 2946

ESP6500EA AF: 0.652 AC: 5604

ExAC AF: 0.675 AC: 81991

Asia WGS AF: 0.723 AC: 2513 AN: 3478

EpiCase AF: 0.682

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	0.069
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.22
DANN	Benign	0.48
DEOGEN2	Benign	0.0020	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.068	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.59
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.63	N
REVEL	Benign	0.0050
Sift	Benign	0.93	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.033
MPC		0.075
ClinPred		0.00013	T
GERP RS		-3.1
Varity_R		0.034
gMVP		0.16
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: rs4918; hg19: chr3-186338382; COSMIC: COSV56607208; COSMIC: COSV56607208;