Genetic Variant NM_003922.4:c.4464-17_4464-16delTT (chr15-63712910-CAA-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003922.4(HERC1):c.4464-17_4464-16delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000469 in 1,278,986 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000047 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HERC1
NM_003922.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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, Labcorp Genetics (formerly Invitae), G2P
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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003922.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC1	NM_003922.4	MANE Select	c.4464-17_4464-16delTT		intron	N/A	NP_003913.3	Q15751

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HERC1	ENST00000443617.7	TSL:1 MANE Select	c.4464-17_4464-16delTT	intron	N/A	ENSP00000390158.2	Q15751
HERC1	ENST00000561400.1	TSL:2	c.1416-17_1416-16delTT	intron	N/A	ENSP00000453937.1	H0YNB1
ENSG00000259589	ENST00000559303.2	TSL:5	n.288-555_288-554delAA	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

143748

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000292

AC:

AN:

137116

AF XY:

0.0000271

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000303

Gnomad OTH exome

AF:

0.000641

GnomAD4 exome

AF:

0.00000469

AC:

AN:

1278986

Hom.:

AF XY:

0.00000315

AC XY:

AN XY:

634480

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28556

American (AMR)

AF:

0.00

AC:

AN:

33040

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21838

East Asian (EAS)

AF:

0.00

AC:

AN:

34062

South Asian (SAS)

AF:

0.00

AC:

AN:

70670

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5048

European-Non Finnish (NFE)

AF:

0.00000607

AC:

AN:

988070

Other (OTH)

AF:

0.00

AC:

AN:

52118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

143748

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69694

African (AFR)

AF:

0.00

AC:

AN:

39176

American (AMR)

AF:

0.00

AC:

AN:

14542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3354

East Asian (EAS)

AF:

0.00

AC:

AN:

4972

South Asian (SAS)

AF:

0.00

AC:

AN:

4542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8908

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65098

Other (OTH)

AF:

0.00

AC:

AN:

1976

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over