15-63648917-A-G

Variant names:

• chr15-63648917-A-G
• rs12439722
• NM_003922.4:c.10748-718T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003922.4(HERC1):​c.10748-718T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 152,288 control chromosomes in the GnomAD database, including 3,935 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (3935 hom., cov: 32)
• Consequence: HERC1 NM_003922.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.765
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.883 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.10748-718T>C		intron	N/A	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.10748-718T>C		intron	N/A	ENSP00000390158.2	Q15751

Frequencies

GnomAD3 genomes AF: 0.151 AC: 23041 AN: 152170 Hom.: 3932 Cov.: 32

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.904

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.173

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.151 AC: 23050 AN: 152288 Hom.: 3935 Cov.: 32 AF XY: 0.164 AC XY: 12198 AN XY: 74474

African (AFR) AF: 0.0324 AC: 1347 AN: 41570

American (AMR) AF: 0.267 AC: 4079 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 475 AN: 3470

East Asian (EAS) AF: 0.905 AC: 4689 AN: 5184

South Asian (SAS) AF: 0.345 AC: 1664 AN: 4826

European-Finnish (FIN) AF: 0.176 AC: 1862 AN: 10604

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.124 AC: 8429 AN: 68018

Other (OTH) AF: 0.173 AC: 365 AN: 2114

Alfa AF: 0.124 Hom.: 320

Bravo AF: 0.158

Asia WGS AF: 0.567 AC: 1971 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.56
DANN	Benign	0.63
PhyloP100		-0.77
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: rs12439722; hg19: chr15-63941116;