Genetic Variant HRCT1:p.Gly50Glu (chr9-35906436-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001039792.2(HRCT1):c.149G>A(p.Gly50Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

HRCT1
NM_001039792.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.993

Variant links:

Genes affected

HRCT1 (HGNC:33872): (histidine rich carboxyl terminus 1) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

HRCT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036960036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRCT1	NM_001039792.2 link	c.149G>A	p.Gly50Glu	missense_variant	Exon 1 of 1	ENST00000354323.3	NP_001034881.1	Q6UXD1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRCT1	ENST00000354323.3 link	c.149G>A	p.Gly50Glu	missense_variant	Exon 1 of 1	6	NM_001039792.2	ENSP00000346283.2		Q6UXD1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460822

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726756

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.000473

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.149G>A (p.G50E) alteration is located in exon 1 (coding exon 1) of the HRCT1 gene. This alteration results from a G to A substitution at nucleotide position 149, causing the glycine (G) at amino acid position 50 to be replaced by a glutamic acid (E). 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

Benign

0.11

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0013

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.42

M_CAP

Benign

0.0021

MetaRNN

Benign

0.037

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.63

REVEL

Benign

0.016

Sift

Benign

0.51

Sift4G

Uncertain

0.030

Polyphen

0.046

Vest4

0.11

MutPred

0.20

Gain of solvent accessibility (P = 0.0456);

MVP

0.040

MPC

0.12

ClinPred

0.14

GERP RS

3.3

Varity_R

0.064

gMVP

0.12

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