Genetic Variant ANHX:p.Arg191His (chr12-133227082-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001372060.1(ANHX):c.572G>A(p.Arg191His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,535,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

ANHX
NM_001372060.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.71

Variant links:

Genes affected

ANHX (HGNC:40024): (anomalous homeobox) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in eye development and regulation of transcription by RNA polymerase II. Predicted to be part of transcription regulator complex. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ANHX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.856

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANHX	NM_001372060.1 link	c.572G>A	p.Arg191His	missense_variant	Exon 5 of 10	ENST00000545940.6	NP_001358989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ANHX	ENST00000545940.6 link	c.572G>A	p.Arg191His	missense_variant	Exon 5 of 10	5	NM_001372060.1	ENSP00000439513.2	A0A6E1YDD0
ANHX	ENST00000419717.3 link	c.572G>A	p.Arg191His	missense_variant	Exon 5 of 9	2		ENSP00000409950.1	E9PGG2
ANHX	ENST00000673940.1 link	c.35G>A	p.Arg12His	missense_variant	Exon 1 of 6			ENSP00000501263.1	A0A669KBG6

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000818

AC:

AN:

134452

Hom.:

AF XY:

0.0000410

AC XY:

AN XY:

73214

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000208

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000167

AC:

231

AN:

1383748

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

100

AN XY:

682826

show subpopulations

Gnomad4 AFR exome

AF:

0.0000633

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000197

Gnomad4 OTH exome

AF:

0.000276

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000553

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.572G>A (p.R191H) alteration is located in exon 5 (coding exon 4) of the ANHX gene. This alteration results from a G to A substitution at nucleotide position 572, causing the arginine (R) at amino acid position 191 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

D;D

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.018

FATHMM_MKL

Benign

0.086

LIST_S2

Uncertain

0.86

D;.

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Pathogenic

3.0

M;M

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-4.3

D;D

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.018

D;D

Polyphen

1.0

D;D

Vest4

0.49

MutPred

0.84

Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);

MVP

0.69

ClinPred

0.93

GERP RS

3.5

Varity_R

0.21

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over