15-63712910-CAAA-CAAAAA

Variant names:

• chr15-63712910-C-CAA
• rs369792267
• NM_003922.4:c.4464-17_4464-16dupTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_003922.4(HERC1):​c.4464-17_4464-16dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,422,610 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (2 hom.)
• Consequence: HERC1 NM_003922.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.01
• Publications: 0 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, Labcorp Genetics (formerly Invitae), G2P
• megalencephaly-severe kyphoscoliosis-overgrowth syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000259589 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 15-63712910-C-CAA is Benign according to our data. Variant chr15-63712910-C-CAA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1191444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00531 (764/143842) while in subpopulation AFR AF = 0.0187 (734/39278). AF 95% confidence interval is 0.0176. There are 9 homozygotes in GnomAd4. There are 382 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.4464-17_4464-16dupTT		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.4464-16_4464-15insTT		intron	N/A	ENSP00000390158.2	Q15751
	HERC1	ENST00000561400.1	TSL:2	c.1416-16_1416-15insTT		intron	N/A	ENSP00000453937.1	H0YNB1
	ENSG00000259589	ENST00000559303.2	TSL:5	n.288-556_288-555insAA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00530 AC: 762 AN: 143740 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0187

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00110

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000220

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000922

Gnomad OTH AF: 0.00354

GnomAD2 exomes AF: 0.00160 AC: 220 AN: 137116 AF XY: 0.00152

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.000447

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000258

Gnomad OTH exome AF: 0.000962

GnomAD4 exome AF: 0.000602 AC: 770 AN: 1278768 Hom.: 2 Cov.: 31 AF XY: 0.000558 AC XY: 354 AN XY: 634360

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0210 AC: 598 AN: 28496

American (AMR) AF: 0.000454 AC: 15 AN: 33042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21838

East Asian (EAS) AF: 0.00 AC: 0 AN: 34054

South Asian (SAS) AF: 0.000212 AC: 15 AN: 70658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45578

Middle Eastern (MID) AF: 0.000991 AC: 5 AN: 5044

European-Non Finnish (NFE) AF: 0.0000587 AC: 58 AN: 987958

Other (OTH) AF: 0.00152 AC: 79 AN: 52100

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00531 AC: 764 AN: 143842 Hom.: 9 Cov.: 32 AF XY: 0.00547 AC XY: 382 AN XY: 69804

African (AFR) AF: 0.0187 AC: 734 AN: 39278

American (AMR) AF: 0.00110 AC: 16 AN: 14562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3354

East Asian (EAS) AF: 0.00 AC: 0 AN: 4960

South Asian (SAS) AF: 0.000221 AC: 1 AN: 4530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000922 AC: 6 AN: 65090

Other (OTH) AF: 0.00350 AC: 7 AN: 2000

Alfa AF: 0.000478 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs369792267; hg19: chr15-64005109;