rs16947363

chr15-63698919-A-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003922.4(HERC1):c.4714T>G(p.Ser1572Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000926 in 1,613,832 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0052 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (7 hom.)
• Consequence: HERC1 NM_003922.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.72

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HERC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0043385625).
• BP6: Variant 15-63698919-A-C is Benign according to our data. Variant chr15-63698919-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 445745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-63698919-A-C is described in Lovd as [Benign]. Variant chr15-63698919-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00522 (795/152346) while in subpopulation AFR AF= 0.0184 (766/41580). AF 95% confidence interval is 0.0173. There are 8 homozygotes in gnomad4. There are 358 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC1	NM_003922.4	c.4714T>G	p.Ser1572Ala	missense_variant	26/78	ENST00000443617.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC1	ENST00000443617.7	c.4714T>G	p.Ser1572Ala	missense_variant	26/78	1	NM_003922.4	P1
	ENST00000559303.2	n.288-14547A>C		intron_variant, non_coding_transcript_variant		5
HERC1	ENST00000561400.1	c.1666T>G	p.Ser556Ala	missense_variant	7/8	2

Frequencies

GnomAD3 genomes AF: 0.00521 AC: 793 AN: 152228 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00136 AC: 338 AN: 249020 Hom.: 4 AF XY: 0.00106 AC XY: 143 AN XY: 135092

Gnomad AFR exome AF: 0.0200

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000621

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000479 AC: 700 AN: 1461486 Hom.: 7 Cov.: 31 AF XY: 0.000399 AC XY: 290 AN XY: 727052

Gnomad4 AFR exome AF: 0.0169

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00522 AC: 795 AN: 152346 Hom.: 8 Cov.: 32 AF XY: 0.00481 AC XY: 358 AN XY: 74492

Gnomad4 AFR AF: 0.0184

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000915 Hom.: 1

Bravo AF: 0.00577

ESP6500AA AF: 0.0191 AC: 71

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00172 AC: 208

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 04, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2022	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.044
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.033
Sift	Uncertain	0.016	D;D
Sift4G	Benign	0.73	T;D
Polyphen		0.0010	B;.
Vest4		0.29
MVP		0.068
MPC		0.28
ClinPred		0.0075	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.26

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: rs16947363; hg19: chr15-63991118;