chr3-186617201-G-T

Position:

• chr3-186617201-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001622.4(AHSG):​c.424G>T​(p.Val142Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000757 in 1,612,028 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (3 hom.)
• Consequence: AHSG NM_001622.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.17

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066143572).
• BP6: Variant 3-186617201-G-T is Benign according to our data. Variant chr3-186617201-G-T is described in ClinVar as [Benign]. Clinvar id is 786026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHSG	NM_001622.4	c.424G>T	p.Val142Leu	missense_variant	4/7	ENST00000411641.7	NP_001613.2
AHSG	NM_001354571.2	c.427G>T	p.Val143Leu	missense_variant	4/7		NP_001341500.1
AHSG	NM_001354572.2	c.421G>T	p.Val141Leu	missense_variant	4/7		NP_001341501.1
AHSG	NM_001354573.2	c.424G>T	p.Val142Leu	missense_variant	4/6		NP_001341502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AHSG	ENST00000411641.7	c.424G>T	p.Val142Leu	missense_variant	4/7	1	NM_001622.4	ENSP00000393887.2

Frequencies

GnomAD3 genomes AF: 0.00393 AC: 598 AN: 152186 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.00105 AC: 263 AN: 250088 Hom.: 1 AF XY: 0.000829 AC XY: 112 AN XY: 135086

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000425 AC: 620 AN: 1459724 Hom.: 3 Cov.: 32 AF XY: 0.000387 AC XY: 281 AN XY: 726012

Gnomad4 AFR exome AF: 0.0152

Gnomad4 AMR exome AF: 0.000627

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.000846

GnomAD4 genome AF: 0.00394 AC: 600 AN: 152304 Hom.: 3 Cov.: 32 AF XY: 0.00362 AC XY: 270 AN XY: 74486

Gnomad4 AFR AF: 0.0137

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.000884 Hom.: 0

Bravo AF: 0.00416

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0141 AC: 62

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00139 AC: 169

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 13, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0066	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.046
Sift	Uncertain	0.0090	D;D
Sift4G	Benign	0.15	T;T
Polyphen		0.12	B;B
Vest4		0.14
MutPred		0.47		.;Gain of helix (P = 0.132);
MVP		0.19
MPC		0.24
ClinPred		0.029	T
GERP RS		3.9
Varity_R		0.14
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7633550; hg19: chr3-186334990;