15-63623587-C-T

Variant names:

• chr15-63623587-C-T
• rs11630290
• NM_003922.4:c.13611+138G>A

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.13611+138G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 799,430 control chromosomes in the GnomAD database, including 19,335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4048 hom., cov: 32)
  • Exomes 𝑓: 0.21 (15287 hom.)
• Consequence: HERC1 NM_003922.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.894
• Publications: 13 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 (BayesDel_noAF=-0.65).
• BP6: Variant 15-63623587-C-T is Benign according to our data. Variant chr15-63623587-C-T is described in ClinVar as Benign. ClinVar VariationId is 1235409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC1	NM_003922.4	MANE Select	c.13611+138G>A		intron	N/A	NP_003913.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC1	ENST00000443617.7	TSL:1 MANE Select	c.13611+138G>A		intron	N/A	ENSP00000390158.2
	HERC1	ENST00000558324.1	TSL:5	n.*316+138G>A		intron	N/A	ENSP00000453196.1

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34000 AN: 152024 Hom.: 4039 Cov.: 32

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.0135

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.193

GnomAD4 exome AF: 0.208 AC: 134861 AN: 647288 Hom.: 15287 AF XY: 0.205 AC XY: 69129 AN XY: 337976

African (AFR) AF: 0.257 AC: 4334 AN: 16884

American (AMR) AF: 0.226 AC: 6141 AN: 27226

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 1957 AN: 15536

East Asian (EAS) AF: 0.0146 AC: 516 AN: 35452

South Asian (SAS) AF: 0.145 AC: 7935 AN: 54582

European-Finnish (FIN) AF: 0.198 AC: 7002 AN: 35424

Middle Eastern (MID) AF: 0.0863 AC: 235 AN: 2722

European-Non Finnish (NFE) AF: 0.235 AC: 100340 AN: 426456

Other (OTH) AF: 0.194 AC: 6401 AN: 33006

GnomAD4 genome AF: 0.224 AC: 34047 AN: 152142 Hom.: 4048 Cov.: 32 AF XY: 0.224 AC XY: 16625 AN XY: 74366

African (AFR) AF: 0.262 AC: 10855 AN: 41498

American (AMR) AF: 0.238 AC: 3634 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 434 AN: 3468

East Asian (EAS) AF: 0.0135 AC: 70 AN: 5188

South Asian (SAS) AF: 0.135 AC: 650 AN: 4812

European-Finnish (FIN) AF: 0.205 AC: 2169 AN: 10564

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15531 AN: 68002

Other (OTH) AF: 0.191 AC: 403 AN: 2112

Alfa AF: 0.223 Hom.: 17849

Bravo AF: 0.226

Asia WGS AF: 0.0840 AC: 292 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	8.3
DANN	Benign	0.85
PhyloP100		-0.89
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11630290; hg19: chr15-63915786;