Genetic Variant HERC1:c.4464-17_4464-16dupTT (chr15-63712910-C-CAA) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_003922.4(HERC1):c.4464-17_4464-16dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,422,610 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0053 ( 9 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 2 hom. )

Consequence

HERC1
NM_003922.4 intron

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 1.01

Publications

0 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:

ENSG00000259589 (HGNC:):

ENSG00000259589 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 15-63712910-C-CAA is Benign according to our data. Variant chr15-63712910-C-CAA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1191444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00531 (764/143842) while in subpopulation AFR AF = 0.0187 (734/39278). AF 95% confidence interval is 0.0176. There are 9 homozygotes in GnomAd4. There are 382 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC1	NM_003922.4 link	c.4464-17_4464-16dupTT		intron_variant	Intron 23 of 77	ENST00000443617.7	NP_003913.3	Q15751A0A024R5W0

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HERC1	ENST00000443617.7 link	c.4464-16_4464-15insTT	intron_variant	Intron 23 of 77	1	NM_003922.4	ENSP00000390158.2	Q15751
HERC1	ENST00000561400.1 link	c.1416-16_1416-15insTT	intron_variant	Intron 4 of 7	2		ENSP00000453937.1	H0YNB1
ENSG00000259589	ENST00000559303.2 link	n.288-556_288-555insAA	intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.00530

AC:

762

AN:

143740

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0187

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00110

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000220

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000922

Gnomad OTH

AF:

0.00354

GnomAD2 exomes

AF:

0.00160

AC:

220

AN:

137116

AF XY:

0.00152

show subpopulations

Gnomad AFR exome

AF:

0.0188

Gnomad AMR exome

AF:

0.000447

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000258

Gnomad OTH exome

AF:

0.000962

GnomAD4 exome

AF:

0.000602

AC:

770

AN:

1278768

Hom.:

Cov.:

AF XY:

0.000558

AC XY:

354

AN XY:

634360

show subpopulations

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

African (AFR)

AF:

0.0210

AC:

598

AN:

28496

American (AMR)

AF:

0.000454

AC:

AN:

33042

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21838

East Asian (EAS)

AF:

0.00

AC:

AN:

34054

South Asian (SAS)

AF:

0.000212

AC:

AN:

70658

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45578

Middle Eastern (MID)

AF:

0.000991

AC:

AN:

5044

European-Non Finnish (NFE)

AF:

0.0000587

AC:

AN:

987958

Other (OTH)

AF:

0.00152

AC:

AN:

52100

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00531

AC:

764

AN:

143842

Hom.:

Cov.:

AF XY:

0.00547

AC XY:

382

AN XY:

69804

show subpopulations

African (AFR)

AF:

0.0187

AC:

734

AN:

39278

American (AMR)

AF:

0.00110

AC:

AN:

14562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3354

East Asian (EAS)

AF:

0.00

AC:

AN:

4960

South Asian (SAS)

AF:

0.000221

AC:

AN:

4530

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8908

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000922

AC:

AN:

65090

Other (OTH)

AF:

0.00350

AC:

AN:

2000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000478

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 12, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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15-63712910-CAAA-CAAAAA

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