15-63712910-CAAA-CAAAAAA

Variant names:

• chr15-63712910-C-CAAA
• rs369792267
• NM_003922.4:c.4464-18_4464-16dupTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003922.4(HERC1):​c.4464-18_4464-16dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000156 in 1,279,304 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: HERC1 NM_003922.4 intron
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC1	NM_003922.4	c.4464-18_4464-16dupTTT		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_4464-15insTTT		intron_variant	Intron 23 of 77	1	NM_003922.4	ENSP00000390158.2
HERC1	ENST00000561400.1	c.1416-16_1416-15insTTT		intron_variant	Intron 4 of 7	2		ENSP00000453937.1
ENSG00000259589	ENST00000559303.2	n.288-556_288-555insAAA		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000156 AC: 2 AN: 1279304 Hom.: 0 Cov.: 31 AF XY: 0.00000158 AC XY: 1 AN XY: 634634

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

African (AFR) AF: 0.0000700 AC: 2 AN: 28558

American (AMR) AF: 0.00 AC: 0 AN: 33058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21848

East Asian (EAS) AF: 0.00 AC: 0 AN: 34062

South Asian (SAS) AF: 0.00 AC: 0 AN: 70702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5048

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 988284

Other (OTH) AF: 0.00 AC: 0 AN: 52136

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0

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;