NM_003922.4:c.14400+170G>C

Variant names:

• chr15-63612081-C-G
• rs62012818
• NM_003922.4:c.14400+170G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003922.4(HERC1):​c.14400+170G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 152,178 control chromosomes in the GnomAD database, including 2,219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.16 (2219 hom., cov: 32)
• Consequence: HERC1 NM_003922.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.75
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 15-63612081-C-G is Benign according to our data. Variant chr15-63612081-C-G is described in ClinVar as Benign. ClinVar VariationId is 1276914.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.199 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.14400+170G>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.14400+170G>C		intron	N/A	ENSP00000390158.2	Q15751

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23766 AN: 152060 Hom.: 2223 Cov.: 32

Gnomad AFR AF: 0.0779

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.242

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.167

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

GnomAD4 genome AF: 0.156 AC: 23756 AN: 152178 Hom.: 2219 Cov.: 32 AF XY: 0.156 AC XY: 11592 AN XY: 74408

African (AFR) AF: 0.0779 AC: 3233 AN: 41512

American (AMR) AF: 0.118 AC: 1802 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 840 AN: 3472

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5186

South Asian (SAS) AF: 0.178 AC: 861 AN: 4824

European-Finnish (FIN) AF: 0.261 AC: 2765 AN: 10582

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13706 AN: 67994

Other (OTH) AF: 0.165 AC: 348 AN: 2106

Alfa AF: 0.108 Hom.: 205

Bravo AF: 0.139

Asia WGS AF: 0.0820 AC: 286 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.0
DANN	Benign	0.16
PhyloP100		-1.7
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: rs62012818; hg19: chr15-63904280;