8-85110101-CTTTTTT-CTTTTTTT

Variant names:

• chr8-85110101-C-CT
• rs755909227
• NM_033402.5:c.311-3dupT

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.311-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0527 in 780,238 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.065 (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 13, offset of 0 (no position change), new splice context is: ttttacttttttttttttAGgac. 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: Variant has high frequency in the SAS (0.0695) population. However there is too low homozygotes in high coverage region: (expected more than 540, got 0).

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.311-3dupT		splice_acceptor intron	N/A	NP_208325.3
	LRRCC1	NM_001349636.2		c.32-3dupT		splice_acceptor intron	N/A	NP_001336565.1
	LRRCC1	NM_001349637.2		c.-158-3dupT		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_311-13insT		intron	N/A	ENSP00000353538.3	Q9C099-1
	LRRCC1	ENST00000414626.2	TSL:1	c.251-14_251-13insT		intron	N/A	ENSP00000394695.2	Q9C099-2
	LRRCC1	ENST00000517875.5	TSL:1	n.105-14_105-13insT		intron	N/A	ENSP00000430960.1	E5RGA4

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 44 AN: 145370 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000343

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000399

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00145

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000228

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0653 AC: 4359 AN: 66706 AF XY: 0.0673

Gnomad AFR exome AF: 0.0493

Gnomad AMR exome AF: 0.0802

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.0755

Gnomad FIN exome AF: 0.0590

Gnomad NFE exome AF: 0.0533

Gnomad OTH exome AF: 0.0814

GnomAD4 exome AF: 0.0646 AC: 41039 AN: 634804 Hom.: 0 Cov.: 8 AF XY: 0.0646 AC XY: 21076 AN XY: 326102

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

African (AFR) AF: 0.0626 AC: 863 AN: 13796

American (AMR) AF: 0.0514 AC: 908 AN: 17670

Ashkenazi Jewish (ASJ) AF: 0.0774 AC: 973 AN: 12574

East Asian (EAS) AF: 0.0630 AC: 1347 AN: 21396

South Asian (SAS) AF: 0.0717 AC: 2942 AN: 41060

European-Finnish (FIN) AF: 0.0563 AC: 1761 AN: 31284

Middle Eastern (MID) AF: 0.0531 AC: 131 AN: 2466

European-Non Finnish (NFE) AF: 0.0647 AC: 30265 AN: 467648

Other (OTH) AF: 0.0687 AC: 1849 AN: 26910

⚠️ 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: 0.000303 AC: 44 AN: 145434 Hom.: 0 Cov.: 33 AF XY: 0.000198 AC XY: 14 AN XY: 70716

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

African (AFR) AF: 0.000225 AC: 9 AN: 39996

American (AMR) AF: 0.000343 AC: 5 AN: 14590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3376

East Asian (EAS) AF: 0.000400 AC: 2 AN: 5000

South Asian (SAS) AF: 0.00 AC: 0 AN: 4616

European-Finnish (FIN) AF: 0.00145 AC: 13 AN: 8970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.000228 AC: 15 AN: 65734

Other (OTH) AF: 0.00 AC: 0 AN: 1980

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000837774), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0271 Hom.: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36
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: rs755909227; hg19: chr8-86022336;