rs80203202

Variant names:

• chr15-63725486-C-T
• rs80203202
• NM_003922.4:c.3374G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003922.4(HERC1):​c.3374G>A​(p.Gly1125Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,613,808 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (6 hom.)
• Consequence: HERC1 NM_003922.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 7.24
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019063026).
• BP6: Variant 15-63725486-C-T is Benign according to our data. Variant chr15-63725486-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 377238.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00211 (321/152164) while in subpopulation NFE AF = 0.00328 (223/68008). AF 95% confidence interval is 0.00293. There are 1 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

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.3374G>A	p.Gly1125Asp	missense	Exon 18 of 78	NP_003913.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC1	ENST00000443617.7	TSL:1 MANE Select	c.3374G>A	p.Gly1125Asp	missense	Exon 18 of 78	ENSP00000390158.2
	HERC1	ENST00000561400.1	TSL:2	c.931-9013G>A		intron	N/A	ENSP00000453937.1

Frequencies

GnomAD3 genomes AF: 0.00211 AC: 321 AN: 152046 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00205 AC: 510 AN: 248816 AF XY: 0.00202

Gnomad AFR exome AF: 0.000646

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00677

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000557

Gnomad NFE exome AF: 0.00285

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00298 AC: 4356 AN: 1461644 Hom.: 6 Cov.: 31 AF XY: 0.00285 AC XY: 2069 AN XY: 727118

African (AFR) AF: 0.000597 AC: 20 AN: 33480

American (AMR) AF: 0.00203 AC: 91 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00700 AC: 183 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000777 AC: 67 AN: 86256

European-Finnish (FIN) AF: 0.000599 AC: 32 AN: 53402

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.00340 AC: 3784 AN: 1111810

Other (OTH) AF: 0.00242 AC: 146 AN: 60374

GnomAD4 genome AF: 0.00211 AC: 321 AN: 152164 Hom.: 1 Cov.: 32 AF XY: 0.00207 AC XY: 154 AN XY: 74394

African (AFR) AF: 0.000554 AC: 23 AN: 41510

American (AMR) AF: 0.00183 AC: 28 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00328 AC: 223 AN: 68008

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00278 Hom.: 3

Bravo AF: 0.00218

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000510 AC: 2

ESP6500EA AF: 0.00302 AC: 25

ExAC AF: 0.00210 AC: 254

EpiCase AF: 0.00344

EpiControl AF: 0.00385

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	HERC1-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	Macrocephaly, dysmorphic facies, and psychomotor retardation (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.18
Sift	Benign	0.23	T
Sift4G	Benign	0.39	T
Polyphen		0.99	D
Vest4		0.85
MVP		0.15
MPC		0.43
ClinPred		0.033	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.62
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs80203202; hg19: chr15-64017685; COSMIC: COSV101497135; COSMIC: COSV101497135;