NM_004667.6:c.1083C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7

The NM_004667.6(HERC2):c.1083C>T(p.His361His) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,591,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

HERC2
NM_004667.6 splice_region, synonymous

Scores

Splicing: ADA: 0.0003077

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.203

Publications

0 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 -11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 15-28272215-G-A is Benign according to our data. Variant chr15-28272215-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 445568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.203 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC2	NM_004667.6 link	c.1083C>T	p.His361His	splice_region_variant, synonymous_variant	Exon 9 of 93	ENST00000261609.13	NP_004658.3	O95714A8KAQ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HERC2	ENST00000261609.13 link	c.1083C>T	p.His361His	splice_region_variant, synonymous_variant	Exon 9 of 93	1	NM_004667.6	ENSP00000261609.8	O95714
HERC2	ENST00000564734.5 link	n.*953C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 10 of 21	1		ENSP00000456237.1	H3BRG9
HERC2	ENST00000564734.5 link	n.*953C>T		3_prime_UTR_variant	Exon 10 of 21	1		ENSP00000456237.1	H3BRG9
HERC2	ENST00000563670.1 link	n.447C>T		non_coding_transcript_exon_variant	Exon 2 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000934

AC:

234

AN:

250436

AF XY:

0.000835

show subpopulations

Gnomad AFR exome

AF:

0.00867

Gnomad AMR exome

AF:

0.000668

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.000656

GnomAD4 exome

AF:

0.0000153

AC:

AN:

1439604

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

714498

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32842

American (AMR)

AF:

0.000145

AC:

AN:

41398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24884

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39488

South Asian (SAS)

AF:

0.0000610

AC:

AN:

82004

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52746

Middle Eastern (MID)

AF:

0.000217

AC:

AN:

4608

European-Non Finnish (NFE)

AF:

0.00000635

AC:

AN:

1102166

Other (OTH)

AF:

0.0000336

AC:

AN:

59468

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.0000131

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41424

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000472

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HERC2: BP4, BP7 -

Jul 19, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.010

(source)

DANN

Benign

0.52

PhyloP100

-0.20

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00031

dbscSNV1_RF

Benign

0.10

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over