15-63609286-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003922.4(HERC1):c.14401-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,588,180 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (11 hom., cov: 33)
  • Exomes 𝑓: 0.012 (126 hom.)
• Consequence: HERC1 NM_003922.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.06

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-63609286-G-A is Benign according to our data. Variant chr15-63609286-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1183226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00885 (1348/152342) while in subpopulation NFE AF= 0.015 (1022/68026). AF 95% confidence interval is 0.0143. There are 11 homozygotes in gnomad4. There are 610 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC1	NM_003922.4	c.14401-20C>T		intron_variant		ENST00000443617.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC1	ENST00000443617.7	c.14401-20C>T		intron_variant		1	NM_003922.4	P1

Frequencies

GnomAD3 genomes AF: 0.00886 AC: 1348 AN: 152224 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00894

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00951 AC: 2157 AN: 226852 Hom.: 19 AF XY: 0.00985 AC XY: 1208 AN XY: 122700

Gnomad AFR exome AF: 0.00229

Gnomad AMR exome AF: 0.00245

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00237

Gnomad FIN exome AF: 0.00810

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0118 AC: 16921 AN: 1435838 Hom.: 126 Cov.: 30 AF XY: 0.0116 AC XY: 8273 AN XY: 710802

Gnomad4 AFR exome AF: 0.00130

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.0132

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00241

Gnomad4 FIN exome AF: 0.00959

Gnomad4 NFE exome AF: 0.0138

Gnomad4 OTH exome AF: 0.00992

GnomAD4 genome AF: 0.00885 AC: 1348 AN: 152342 Hom.: 11 Cov.: 33 AF XY: 0.00819 AC XY: 610 AN XY: 74490

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00894

Gnomad4 NFE AF: 0.0150

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00681 Hom.: 6

Bravo AF: 0.00767

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	15
Dann	Benign	0.61

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

LitVar

Other links and lift over

dbSNP: rs147469276; hg19: chr15-63901485;