Genetic Variant HRCT1:p.Gly65Ser (chr9-35906480-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001039792.2(HRCT1):c.193G>A(p.Gly65Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,606,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. G65D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HRCT1
NM_001039792.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.50

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22916564).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039792.2. 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
	HRCT1	NM_001039792.2	MANE Select	c.193G>A	p.Gly65Ser	missense	Exon 1 of 1	NP_001034881.1	Q6UXD1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRCT1	ENST00000354323.3	TSL:6 MANE Select	c.193G>A	p.Gly65Ser	missense	Exon 1 of 1	ENSP00000346283.2	Q6UXD1

Frequencies

GnomAD3 genomes

AF:

0.00000668

AC:

AN:

149794

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1457100

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724840

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33324

American (AMR)

AF:

0.00

AC:

AN:

44584

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26018

East Asian (EAS)

AF:

0.00

AC:

AN:

39338

South Asian (SAS)

AF:

0.00

AC:

AN:

86176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51982

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1109818

Other (OTH)

AF:

0.00

AC:

AN:

60122

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000668

AC:

AN:

149794

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73084

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40682

American (AMR)

AF:

0.00

AC:

AN:

14968

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3438

East Asian (EAS)

AF:

0.00

AC:

AN:

5048

South Asian (SAS)

AF:

0.00

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

302

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67328

Other (OTH)

AF:

0.00

AC:

AN:

2046

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0041

Eigen

Benign

0.0058

Eigen_PC

Benign

-0.054

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.51

M_CAP

Benign

0.0022

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

2.5

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.13

Sift

Benign

0.13

Sift4G

Benign

0.68

Polyphen

1.0

Vest4

0.42

MutPred

0.14

Gain of glycosylation at G65 (P = 0.025)

MVP

0.095

MPC

0.11

ClinPred

0.91

GERP RS

2.9

PromoterAI

0.017

Neutral

(source)

Varity_R

0.084

gMVP

0.23

Mutation Taster

=91/9

polymorphism

(source)

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over