Genetic Variant NM_001622.4:c.767G>T (chr3-186620593-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001622.4(AHSG):c.767G>T(p.Ser256Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S256T) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

AHSG
NM_001622.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.591

Publications

0 publications found

Variant links:

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]

AHSG links:

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

HRG-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0456644).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AHSG	NM_001622.4	MANE Select	c.767G>T	p.Ser256Ile	missense	Exon 7 of 7	NP_001613.2
AHSG	NM_001354571.2		c.770G>T	p.Ser257Ile	missense	Exon 7 of 7	NP_001341500.1
AHSG	NM_001354572.2		c.764G>T	p.Ser255Ile	missense	Exon 7 of 7	NP_001341501.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AHSG	ENST00000411641.7	TSL:1 MANE Select	c.767G>T	p.Ser256Ile	missense	Exon 7 of 7	ENSP00000393887.2
AHSG	ENST00000273784.5	TSL:3	c.770G>T	p.Ser257Ile	missense	Exon 7 of 7	ENSP00000273784.5
HRG-AS1	ENST00000625386.2	TSL:5	n.388+21361C>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441900

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712916

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33146

American (AMR)

AF:

0.00

AC:

AN:

43986

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25634

East Asian (EAS)

AF:

0.00

AC:

AN:

39160

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85620

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1096158

Other (OTH)

AF:

0.00

AC:

AN:

59372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.86

(source)

DANN

Benign

0.25

DEOGEN2

Benign

0.0023

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.14

M_CAP

Benign

0.0037

MetaRNN

Benign

0.046

MetaSVM

Benign

-0.96

PhyloP100

-0.59

PrimateAI

Benign

0.31

PROVEAN

Benign

1.2

REVEL

Benign

0.010

Sift

Benign

0.64

Sift4G

Benign

0.46

Polyphen

0.0

Vest4

0.088

MutPred

0.34

Loss of disorder (P = 0.0127)

MVP

0.13

MPC

0.097

ClinPred

0.030

GERP RS

-3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.030

gMVP

0.18

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over