Genetic Variant HRNR:p.Arg2677His (chr1-152213599-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001009931.3(HRNR):c.8030G>A(p.Arg2677His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 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. R2677P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 10)

Exomes 𝑓: 0.00012 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

HRNR
NM_001009931.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.25

Publications

0 publications found

Variant links:

Genes affected

HRNR (HGNC:20846): (hornerin) Predicted to enable calcium ion binding activity and transition metal ion binding activity. Involved in cell envelope organization and establishment of skin barrier. Located in cornified envelope; keratohyalin granule; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

HRNR links:

CCDST (HGNC:55988): (cervical cancer associated DHX9 suppressive transcript)

CCDST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013763815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRNR	NM_001009931.3 link	c.8030G>A	p.Arg2677His	missense_variant	Exon 3 of 3	ENST00000368801.4	NP_001009931.1	Q86YZ3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRNR	ENST00000368801.4 link	c.8030G>A	p.Arg2677His	missense_variant	Exon 3 of 3	1	NM_001009931.3	ENSP00000357791.3		Q86YZ3

Frequencies

GnomAD3 genomes

AF:

0.000133

AC:

AN:

67736

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000224

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:

0.0106

Gnomad NFE

AF:

0.000122

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000398

AC:

AN:

95516

AF XY:

0.000344

show subpopulations

Gnomad AFR exome

AF:

0.000600

Gnomad AMR exome

AF:

0.00163

Gnomad ASJ exome

AF:

0.00305

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000113

Gnomad OTH exome

AF:

0.000451

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000115

AC:

126

AN:

1094390

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

549604

show subpopulations

African (AFR)

AF:

0.000279

AC:

AN:

25070

American (AMR)

AF:

0.000585

AC:

AN:

30788

Ashkenazi Jewish (ASJ)

AF:

0.00161

AC:

AN:

18612

East Asian (EAS)

AF:

0.00

AC:

AN:

36034

South Asian (SAS)

AF:

0.0000692

AC:

AN:

72228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45178

Middle Eastern (MID)

AF:

0.000262

AC:

AN:

3816

European-Non Finnish (NFE)

AF:

0.0000539

AC:

AN:

815952

Other (OTH)

AF:

0.000450

AC:

AN:

46712

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000133

AC:

AN:

67794

Hom.:

Cov.:

AF XY:

0.000123

AC XY:

AN XY:

32480

show subpopulations

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

African (AFR)

AF:

0.000223

AC:

AN:

17946

American (AMR)

AF:

0.00

AC:

AN:

5284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1442

East Asian (EAS)

AF:

0.00

AC:

AN:

2734

South Asian (SAS)

AF:

0.00

AC:

AN:

1846

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4396

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000122

AC:

AN:

32890

Other (OTH)

AF:

0.00

AC:

AN:

794

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0136520), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.381

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000371

Hom.:

ExAC

AF:

0.000107

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.76

CADD

Benign

6.3

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.013

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.00091

LIST_S2

Benign

0.25

M_CAP

Benign

0.0021

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

PhyloP100

-1.2

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.40

REVEL

Benign

0.0050

Sift

Benign

0.14

Sift4G

Uncertain

0.043

Polyphen

0.0010

Vest4

0.16

MutPred

0.30

Loss of MoRF binding (P = 0.0049);

MVP

0.20

ClinPred

0.0024

GERP RS

-0.93

Varity_R

0.018

gMVP

0.028

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over