Genetic Variant NM_001009931.3:c.8030G>A (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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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