NM_003922.4:c.11166G>C

Variant names:

• chr15-63645010-C-G
• rs2229749
• NM_003922.4:c.11166G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E3722E) has been classified as Likely benign.

• 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
• Publications: 32 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId 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.

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.11166G>C	p.Glu3722Asp	missense	Exon 57 of 78	NP_003913.3	Q15751

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC1	ENST00000443617.7	TSL:1 MANE Select	c.11166G>C	p.Glu3722Asp	missense	Exon 57 of 78	ENSP00000390158.2	Q15751

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

GnomAD2 exomes AF: 0.739 AC: 184014 AN: 249060 AF XY: 0.745

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 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

African (AFR) AF: 0.852 AC: 28492 AN: 33434

American (AMR) AF: 0.577 AC: 25801 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.861 AC: 22479 AN: 26112

East Asian (EAS) AF: 0.0843 AC: 3343 AN: 39658

South Asian (SAS) AF: 0.643 AC: 55428 AN: 86186

European-Finnish (FIN) AF: 0.834 AC: 44511 AN: 53386

Middle Eastern (MID) AF: 0.833 AC: 4801 AN: 5766

European-Non Finnish (NFE) AF: 0.879 AC: 975053 AN: 1109900

Other (OTH) AF: 0.800 AC: 48229 AN: 60280

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

African (AFR) AF: 0.852 AC: 35332 AN: 41476

American (AMR) AF: 0.723 AC: 11040 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.859 AC: 2982 AN: 3472

East Asian (EAS) AF: 0.0957 AC: 495 AN: 5174

South Asian (SAS) AF: 0.603 AC: 2903 AN: 4818

European-Finnish (FIN) AF: 0.825 AC: 8719 AN: 10568

Middle Eastern (MID) AF: 0.864 AC: 254 AN: 294

European-Non Finnish (NFE) AF: 0.876 AC: 59545 AN: 68004

Other (OTH) AF: 0.807 AC: 1705 AN: 2112

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Macrocephaly, dysmorphic facies, and psychomotor retardation (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.20
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2229749; hg19: chr15-63937209; COSMIC: COSV71246767;