ENST00000414626.2:c.44G>A

Variant names:

• chr8-85109594-G-A
• rs886039794
• ENST00000414626.2:c.44G>A
• LRRCC1 p.Ser15Asn

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The ENST00000414626.2(LRRCC1):​c.44G>A​(p.Ser15Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000215 in 1,398,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S15T) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LRRCC1 ENST00000414626.2 missense
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.17
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-85109594-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 266077.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000414626.2. 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.105-1G>A		splice_acceptor intron	N/A	NP_208325.3
	LRRCC1	NM_001349636.2		c.32-521G>A		intron	N/A	NP_001336565.1
	LRRCC1	NM_001349637.2		c.-158-521G>A		intron	N/A	NP_001336566.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRCC1	ENST00000414626.2	TSL:1	c.44G>A	p.Ser15Asn	missense	Exon 1 of 18	ENSP00000394695.2	Q9C099-2
	LRRCC1	ENST00000360375.8	TSL:1 MANE Select	c.105-1G>A		splice_acceptor intron	N/A	ENSP00000353538.3	Q9C099-1
	LRRCC1	ENST00000517875.5	TSL:1	n.105-521G>A		intron	N/A	ENSP00000430960.1	E5RGA4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1398332 Hom.: 0 Cov.: 25 AF XY: 0.00000287 AC XY: 2 AN XY: 696412

African (AFR) AF: 0.00 AC: 0 AN: 31606

American (AMR) AF: 0.00 AC: 0 AN: 41918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25444

East Asian (EAS) AF: 0.00 AC: 0 AN: 38180

South Asian (SAS) AF: 0.00 AC: 0 AN: 81366

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51770

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5560

European-Non Finnish (NFE) AF: 0.00000282 AC: 3 AN: 1064568

Other (OTH) AF: 0.00 AC: 0 AN: 57920

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.033	D
PhyloP100		7.2
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.75		Position offset: 21
DS_AL_spliceai		0.99		Position offset: 1

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.

Other links and lift over

dbSNP: rs886039794;

hg19: chr8-86021829;