dbSNP rs11630290: HERC1:c.13611+138G>A (chr15-63623587-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003922.4(HERC1):c.13611+138G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 799,430 control chromosomes in the GnomAD database, including 19,335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4048 hom., cov: 32)

Exomes 𝑓: 0.21 ( 15287 hom. )

Consequence

HERC1
NM_003922.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.894

Publications

13 publications found

Variant links:

Genes affected

HERC1 (HGNC:4867): (HECT and RLD domain containing E3 ubiquitin protein ligase family member 1) This gen encodes a member of the HERC protein family. This protein stimulates guanine nucleotide exchange on ARF1 and Rab proteins. This protein may be involved in membrane transport processes. [provided by RefSeq, Mar 2012]

HERC1 Gene-Disease associations (from GenCC):

macrocephaly, dysmorphic facies, and psychomotor retardation
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
megalencephaly-severe kyphoscoliosis-overgrowth syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HERC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

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

BP6

Variant 15-63623587-C-T is Benign according to our data. Variant chr15-63623587-C-T is described in ClinVar as Benign. ClinVar VariationId is 1235409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC1	NM_003922.4 link	c.13611+138G>A		intron_variant	Intron 73 of 77	ENST00000443617.7	NP_003913.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC1	ENST00000443617.7 link	c.13611+138G>A		intron_variant	Intron 73 of 77	1	NM_003922.4	ENSP00000390158.2
HERC1	ENST00000558324.1 link	n.*316+138G>A		intron_variant	Intron 5 of 5	5		ENSP00000453196.1

Frequencies

GnomAD3 genomes

AF:

0.224

AC:

34000

AN:

152024

Hom.:

4039

Cov.:

show subpopulations

Gnomad AFR

AF:

0.261

Gnomad AMI

AF:

0.308

Gnomad AMR

AF:

0.238

Gnomad ASJ

AF:

0.125

Gnomad EAS

AF:

0.0135

Gnomad SAS

AF:

0.134

Gnomad FIN

AF:

0.205

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.228

Gnomad OTH

AF:

0.193

GnomAD4 exome

AF:

0.208

AC:

134861

AN:

647288

Hom.:

15287

AF XY:

0.205

AC XY:

69129

AN XY:

337976

show subpopulations

African (AFR)

AF:

0.257

AC:

4334

AN:

16884

American (AMR)

AF:

0.226

AC:

6141

AN:

27226

Ashkenazi Jewish (ASJ)

AF:

0.126

AC:

1957

AN:

15536

East Asian (EAS)

AF:

0.0146

AC:

516

AN:

35452

South Asian (SAS)

AF:

0.145

AC:

7935

AN:

54582

European-Finnish (FIN)

AF:

0.198

AC:

7002

AN:

35424

Middle Eastern (MID)

AF:

0.0863

AC:

235

AN:

2722

European-Non Finnish (NFE)

AF:

0.235

AC:

100340

AN:

426456

Other (OTH)

AF:

0.194

AC:

6401

AN:

33006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

5198

10396

15593

20791

25989

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1854

3708

5562

7416

9270

<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:

0.224

AC:

34047

AN:

152142

Hom.:

4048

Cov.:

AF XY:

0.224

AC XY:

16625

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.262

AC:

10855

AN:

41498

American (AMR)

AF:

0.238

AC:

3634

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

434

AN:

3468

East Asian (EAS)

AF:

0.0135

AC:

AN:

5188

South Asian (SAS)

AF:

0.135

AC:

650

AN:

4812

European-Finnish (FIN)

AF:

0.205

AC:

2169

AN:

10564

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.228

AC:

15531

AN:

68002

Other (OTH)

AF:

0.191

AC:

403

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1389

2778

4166

5555

6944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

354

708

1062

1416

1770

<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:

0.223

Hom.:

17849

Bravo

AF:

0.226

Asia WGS

AF:

0.0840

AC:

292

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 06, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

8.3

(source)

DANN

Benign

0.85

PhyloP100

-0.89

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over