chr8-85110101-C-CTTTT

Variant names:

• chr8-85110101-C-CTTTT
• rs755909227
• NM_033402.5:c.311-6_311-3dupTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_033402.5(LRRCC1):​c.311-6_311-3dupTTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 708,266 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: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LRRCC1 NM_033402.5 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.363
• Publications: 0 publications found

Genes affected

LRRCC1 (HGNC:29373): (leucine rich repeat and coiled-coil centrosomal protein 1) This gene encodes a centrosomal protein that maintains the structural integrity of the centrosome and plays a key role in mitotic spindle formation. The encoded protein contains an N-terminal leucine-rich repeat domain and a C-terminal coiled-coil domain. It associates with the centrosome throughout the cell cycle and accumulates on the mitotic centrosome. [provided by RefSeq, Mar 2017]

E2F5-DT (HGNC:55393): (E2F5 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.021297192 fraction of the gene. Cryptic splice site detected, with MaxEntScore 12, offset of 0 (no position change), new splice context is: tactttttttttttttttAGgac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033402.5. 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
	LRRCC1	NM_033402.5	MANE Select	c.311-6_311-3dupTTTT		splice_acceptor intron	N/A	NP_208325.3
	LRRCC1	NM_001349636.2		c.32-6_32-3dupTTTT		splice_acceptor intron	N/A	NP_001336565.1
	LRRCC1	NM_001349637.2		c.-158-6_-158-3dupTTTT		splice_acceptor intron	N/A	NP_001336566.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRCC1	ENST00000360375.8	TSL:1 MANE Select	c.311-14_311-13insTTTT		intron	N/A	ENSP00000353538.3	Q9C099-1
	LRRCC1	ENST00000414626.2	TSL:1	c.251-14_251-13insTTTT		intron	N/A	ENSP00000394695.2	Q9C099-2
	LRRCC1	ENST00000517875.5	TSL:1	n.105-14_105-13insTTTT		intron	N/A	ENSP00000430960.1	E5RGA4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000141 AC: 1 AN: 708266 Hom.: 0 Cov.: 8 AF XY: 0.00000273 AC XY: 1 AN XY: 365936

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

African (AFR) AF: 0.00 AC: 0 AN: 15526

American (AMR) AF: 0.00 AC: 0 AN: 19816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14898

East Asian (EAS) AF: 0.00 AC: 0 AN: 25670

South Asian (SAS) AF: 0.00 AC: 0 AN: 46110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2790

European-Non Finnish (NFE) AF: 0.00000193 AC: 1 AN: 517208

Other (OTH) AF: 0.00 AC: 0 AN: 31010

⚠️ 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 Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36

Splicing

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

Other links and lift over

dbSNP: rs755909227; hg19: chr8-86022336;