15-63712910-CAAA-CAAAA

Variant names:

• chr15-63712910-C-CA
• rs369792267
• NM_003922.4:c.4464-16dupT

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.4464-16dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00534 in 1,372,942 control chromosomes in the GnomAD database, including 54 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (21 hom.)
• Consequence: HERC1 NM_003922.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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, G2P, Labcorp Genetics (formerly Invitae)
• 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-CA is Benign according to our data. Variant chr15-63712910-C-CA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445682.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 = 0.013 (1872/143812) while in subpopulation AFR AF = 0.0456 (1790/39272). AF 95% confidence interval is 0.0438. There are 33 homozygotes in GnomAd4. There are 858 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC1	NM_003922.4	c.4464-16dupT		intron_variant	Intron 23 of 77	ENST00000443617.7	NP_003913.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC1	ENST00000443617.7	c.4464-16_4464-15insT		intron_variant	Intron 23 of 77	1	NM_003922.4	ENSP00000390158.2
HERC1	ENST00000561400.1	c.1416-16_1416-15insT		intron_variant	Intron 4 of 7	2		ENSP00000453937.1
ENSG00000259589	ENST00000559303.2	n.288-556_288-555insA		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1863 AN: 143712 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.0455

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.000298

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000220

Gnomad FIN AF: 0.000337

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000184

Gnomad OTH AF: 0.0142

GnomAD2 exomes AF: 0.0111 AC: 1521 AN: 137116 AF XY: 0.00965

Gnomad AFR exome AF: 0.0651

Gnomad AMR exome AF: 0.0112

Gnomad ASJ exome AF: 0.00799

Gnomad EAS exome AF: 0.00579

Gnomad FIN exome AF: 0.00867

Gnomad NFE exome AF: 0.00514

Gnomad OTH exome AF: 0.00994

GnomAD4 exome AF: 0.00444 AC: 5458 AN: 1229130 Hom.: 21 Cov.: 31 AF XY: 0.00426 AC XY: 2600 AN XY: 609674

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

African (AFR) AF: 0.0559 AC: 1542 AN: 27574

American (AMR) AF: 0.00803 AC: 255 AN: 31738

Ashkenazi Jewish (ASJ) AF: 0.00455 AC: 95 AN: 20902

East Asian (EAS) AF: 0.00333 AC: 108 AN: 32390

South Asian (SAS) AF: 0.00349 AC: 236 AN: 67548

European-Finnish (FIN) AF: 0.00517 AC: 228 AN: 44130

Middle Eastern (MID) AF: 0.00711 AC: 35 AN: 4924

European-Non Finnish (NFE) AF: 0.00275 AC: 2617 AN: 949950

Other (OTH) AF: 0.00684 AC: 342 AN: 49974

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0130 AC: 1872 AN: 143812 Hom.: 33 Cov.: 32 AF XY: 0.0123 AC XY: 858 AN XY: 69792

African (AFR) AF: 0.0456 AC: 1790 AN: 39272

American (AMR) AF: 0.00254 AC: 37 AN: 14558

Ashkenazi Jewish (ASJ) AF: 0.000298 AC: 1 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: 0.000337 AC: 3 AN: 8902

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

European-Non Finnish (NFE) AF: 0.000184 AC: 12 AN: 65076

Other (OTH) AF: 0.0140 AC: 28 AN: 2000

Alfa AF: 0.0135 Hom.: 0

Bravo AF: 0.0141

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Aug 21, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 09, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 20, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

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: rs369792267; hg19: chr15-64005109;