Genetic Variant NM_004667.6:c.1084-70G>A (chr15-28270938-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004667.6(HERC2):c.1084-70G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.776 in 1,370,128 control chromosomes in the GnomAD database, including 438,843 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.65 ( 37311 hom., cov: 33)

Exomes 𝑓: 0.79 ( 401532 hom. )

Consequence

HERC2
NM_004667.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.302

Publications

18 publications found

Variant links:

Genes affected

HERC2 (HGNC:4868): (HECT and RLD domain containing E3 ubiquitin protein ligase 2) This gene belongs to the HERC gene family that encodes a group of unusually large proteins, which contain multiple structural domains. All members have at least 1 copy of an N-terminal region showing homology to the cell cycle regulator RCC1 and a C-terminal HECT (homologous to E6-AP C terminus) domain found in a number of E3 ubiquitin protein ligases. Genetic variations in this gene are associated with skin/hair/eye pigmentation variability. Multiple pseudogenes of this gene are located on chromosomes 15 and 16. [provided by RefSeq, Mar 2012]

HERC2 Gene-Disease associations (from GenCC):

developmental delay with autism spectrum disorder and gait instability
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

HERC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC2	NM_004667.6 link	c.1084-70G>A		intron_variant	Intron 9 of 92	ENST00000261609.13	NP_004658.3	O95714A8KAQ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC2	ENST00000261609.13 link	c.1084-70G>A		intron_variant	Intron 9 of 92	1	NM_004667.6	ENSP00000261609.8		O95714
HERC2	ENST00000564734.5 link	n.*954-70G>A		intron_variant	Intron 10 of 20	1		ENSP00000456237.1		H3BRG9

Frequencies

GnomAD3 genomes

AF:

0.649

AC:

98690

AN:

151986

Hom.:

37319

Cov.:

show subpopulations

Gnomad AFR

AF:

0.298

Gnomad AMI

AF:

0.666

Gnomad AMR

AF:

0.610

Gnomad ASJ

AF:

0.763

Gnomad EAS

AF:

0.266

Gnomad SAS

AF:

0.427

Gnomad FIN

AF:

0.969

Gnomad MID

AF:

0.598

Gnomad NFE

AF:

0.862

Gnomad OTH

AF:

0.621

GnomAD4 exome

AF:

0.792

AC:

964831

AN:

1218024

Hom.:

401532

AF XY:

0.782

AC XY:

477529

AN XY:

610762

show subpopulations

African (AFR)

AF:

0.277

AC:

7810

AN:

28174

American (AMR)

AF:

0.597

AC:

21066

AN:

35290

Ashkenazi Jewish (ASJ)

AF:

0.772

AC:

18051

AN:

23370

East Asian (EAS)

AF:

0.255

AC:

9167

AN:

36016

South Asian (SAS)

AF:

0.432

AC:

32203

AN:

74564

European-Finnish (FIN)

AF:

0.967

AC:

48354

AN:

49990

Middle Eastern (MID)

AF:

0.572

AC:

2106

AN:

3680

European-Non Finnish (NFE)

AF:

0.862

AC:

788169

AN:

914852

Other (OTH)

AF:

0.728

AC:

37905

AN:

52088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

8502

17004

25505

34007

42509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16228

32456

48684

64912

81140

<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:

0.649

AC:

98686

AN:

152104

Hom.:

37311

Cov.:

AF XY:

0.644

AC XY:

47898

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.298

AC:

12332

AN:

41448

American (AMR)

AF:

0.610

AC:

9319

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.763

AC:

2647

AN:

3470

East Asian (EAS)

AF:

0.266

AC:

1370

AN:

5158

South Asian (SAS)

AF:

0.427

AC:

2056

AN:

4810

European-Finnish (FIN)

AF:

0.969

AC:

10294

AN:

10622

Middle Eastern (MID)

AF:

0.595

AC:

175

AN:

294

European-Non Finnish (NFE)

AF:

0.862

AC:

58583

AN:

67998

Other (OTH)

AF:

0.617

AC:

1304

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1262

2524

3785

5047

6309

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

736

1472

2208

2944

3680

<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:

0.766

Hom.:

31621

Bravo

AF:

0.609

Asia WGS

AF:

0.389

AC:

1353

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

6.5

(source)

DANN

Benign

0.38

PhyloP100

0.30

Mutation Taster

=100/0

polymorphism (auto)

(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