rs2229749

Positions:

• chr15-63645010-C-G
• chr15-63645010-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_003922.4(HERC1):​c.11166G>C​(p.Glu3722Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.826 in 1,611,522 control chromosomes in the GnomAD database, including 569,108 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.81 (52232 hom., cov: 31)
  • Exomes 𝑓: 0.83 (516876 hom.)
• Consequence: HERC1 NM_003922.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.198

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 -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HERC1. . Gene score misZ 4.9558 (greater than the threshold 3.09). Trascript score misZ 5.2706 (greater than threshold 3.09). GenCC has associacion of gene with macrocephaly, dysmorphic facies, and psychomotor retardation, megalencephaly-severe kyphoscoliosis-overgrowth syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=6.446062E-7).
• BP6: Variant 15-63645010-C-G is Benign according to our data. Variant chr15-63645010-C-G is described in ClinVar as [Benign]. Clinvar id is 1243466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.87 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HERC1	NM_003922.4	c.11166G>C	p.Glu3722Asp	missense_variant	57/78	ENST00000443617.7	NP_003913.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HERC1	ENST00000443617.7	c.11166G>C	p.Glu3722Asp	missense_variant	57/78	1	NM_003922.4	ENSP00000390158	P1

Frequencies

GnomAD3 genomes AF: 0.814 AC: 123679 AN: 151980 Hom.: 52185 Cov.: 31

Gnomad AFR AF: 0.852

Gnomad AMI AF: 0.887

Gnomad AMR AF: 0.724

Gnomad ASJ AF: 0.859

Gnomad EAS AF: 0.0958

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.825

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.876

Gnomad OTH AF: 0.806

GnomAD3 exomes AF: 0.739 AC: 184014 AN: 249060 Hom.: 74402 AF XY: 0.745 AC XY: 100673 AN XY: 135112

Gnomad AFR exome AF: 0.851

Gnomad AMR exome AF: 0.553

Gnomad ASJ exome AF: 0.862

Gnomad EAS exome AF: 0.0824

Gnomad SAS exome AF: 0.644

Gnomad FIN exome AF: 0.829

Gnomad NFE exome AF: 0.879

Gnomad OTH exome AF: 0.803

GnomAD4 exome AF: 0.828 AC: 1208137 AN: 1459424 Hom.: 516876 Cov.: 33 AF XY: 0.824 AC XY: 598206 AN XY: 726170

Gnomad4 AFR exome AF: 0.852

Gnomad4 AMR exome AF: 0.577

Gnomad4 ASJ exome AF: 0.861

Gnomad4 EAS exome AF: 0.0843

Gnomad4 SAS exome AF: 0.643

Gnomad4 FIN exome AF: 0.834

Gnomad4 NFE exome AF: 0.879

Gnomad4 OTH exome AF: 0.800

GnomAD4 genome AF: 0.814 AC: 123782 AN: 152098 Hom.: 52232 Cov.: 31 AF XY: 0.802 AC XY: 59596 AN XY: 74354

Gnomad4 AFR AF: 0.852

Gnomad4 AMR AF: 0.723

Gnomad4 ASJ AF: 0.859

Gnomad4 EAS AF: 0.0957

Gnomad4 SAS AF: 0.603

Gnomad4 FIN AF: 0.825

Gnomad4 NFE AF: 0.876

Gnomad4 OTH AF: 0.807

Alfa AF: 0.834 Hom.: 29651

Bravo AF: 0.803

TwinsUK AF: 0.876 AC: 3248

ALSPAC AF: 0.873 AC: 3365

ESP6500AA AF: 0.857 AC: 3337

ESP6500EA AF: 0.880 AC: 7302

ExAC AF: 0.747 AC: 90265

Asia WGS AF: 0.404 AC: 1406 AN: 3478

EpiCase AF: 0.877

EpiControl AF: 0.880

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Macrocephaly, dysmorphic facies, and psychomotor retardation Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	14
DANN	Benign	0.14
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	6.4e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.55	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.049
Sift	Benign	0.72	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.0090
MutPred		0.19		Loss of disorder (P = 0.1792);
MPC		0.30
ClinPred		0.0014	T
GERP RS		-3.3
Varity_R		0.038
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2229749; hg19: chr15-63937209; COSMIC: COSV71246767;