Genetic Variant NM_033402.5:c.311-4_311-3dupTT (chr8-85110101-C-CTT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_033402.5(LRRCC1):c.311-4_311-3dupTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LRRCC1
NM_033402.5 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.363

Publications

0 publications found

Variant links:

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]

LRRCC1 links:

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

E2F5-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 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: tttactttttttttttttAGgac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
LRRCC1	NM_033402.5	MANE Select	c.311-4_311-3dupTT	splice_acceptor intron	N/A	NP_208325.3
LRRCC1	NM_001349636.2		c.32-4_32-3dupTT	splice_acceptor intron	N/A	NP_001336565.1
LRRCC1	NM_001349637.2		c.-158-4_-158-3dupTT	splice_acceptor intron	N/A	NP_001336566.1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

145466

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000435

AC:

AN:

66706

AF XY:

0.000498

show subpopulations

Gnomad AFR exome

AF:

0.000611

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.000447

Gnomad EAS exome

AF:

0.00151

Gnomad FIN exome

AF:

0.000301

Gnomad NFE exome

AF:

0.000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000322

AC:

227

AN:

705650

Hom.:

Cov.:

AF XY:

0.000277

AC XY:

101

AN XY:

364590

show subpopulations

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

African (AFR)

AF:

0.000323

AC:

AN:

15468

American (AMR)

AF:

0.000101

AC:

AN:

19750

Ashkenazi Jewish (ASJ)

AF:

0.000337

AC:

AN:

14844

East Asian (EAS)

AF:

0.000352

AC:

AN:

25562

South Asian (SAS)

AF:

0.000480

AC:

AN:

45820

European-Finnish (FIN)

AF:

0.000114

AC:

AN:

35116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2788

European-Non Finnish (NFE)

AF:

0.000332

AC:

171

AN:

515402

Other (OTH)

AF:

0.000291

AC:

AN:

30900

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.239

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

145466

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70700

African (AFR)

AF:

0.00

AC:

AN:

39908

American (AMR)

AF:

0.00

AC:

AN:

14576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3376

East Asian (EAS)

AF:

0.00

AC:

AN:

5016

South Asian (SAS)

AF:

0.00

AC:

AN:

4634

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9000

Middle Eastern (MID)

AF:

0.00

AC:

AN:

302

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65796

Other (OTH)

AF:

0.00

AC:

AN:

1966

Alfa

AF:

0.000235

Hom.:

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over