4-56011797-C-A

Variant names:

• chr4-56011797-C-A
• rs377744366
• NM_025009.5:c.2617-3C>A

Variant summary

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

The NM_025009.5(CEP135):​c.2617-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,412,852 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CEP135 NM_025009.5 splice_region, intron
• Scores: Splicing: ADA: 0.8964
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.631
• Publications: 0 publications found

Genes affected

CEP135 (HGNC:29086): (centrosomal protein 135) This gene encodes a centrosomal protein, which acts as a scaffolding protein during early centriole biogenesis, and is also required for centriole-centriole cohesion during interphase. Mutations in this gene are associated with autosomal recessive primary microcephaly-8. [provided by RefSeq, Jun 2012]

CEP135 Gene-Disease associations (from GenCC):

• microcephaly 8, primary, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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
CEP135	NM_025009.5	c.2617-3C>A		splice_region_variant, intron_variant	Intron 20 of 25	ENST00000257287.5	NP_079285.2
CEP135	XM_006714055.4	c.2584-3C>A		splice_region_variant, intron_variant	Intron 20 of 25		XP_006714118.1
CEP135	XM_005265788.5	c.1546-3C>A		splice_region_variant, intron_variant	Intron 13 of 18		XP_005265845.1
CEP135	XM_011534412.2	c.1087-3C>A		splice_region_variant, intron_variant	Intron 10 of 15		XP_011532714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP135	ENST00000257287.5	c.2617-3C>A		splice_region_variant, intron_variant	Intron 20 of 25	1	NM_025009.5	ENSP00000257287.3
CEP135	ENST00000506202.1	n.2567-3C>A		splice_region_variant, intron_variant	Intron 13 of 18	1
CEP135	ENST00000706801.1	n.682-3C>A		splice_region_variant, intron_variant	Intron 4 of 9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000481 AC: 1 AN: 207864 AF XY: 0.00000882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000998

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1412852 Hom.: 0 Cov.: 31 AF XY: 0.00000285 AC XY: 2 AN XY: 701596

African (AFR) AF: 0.00 AC: 0 AN: 30336

American (AMR) AF: 0.00 AC: 0 AN: 31442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23660

East Asian (EAS) AF: 0.00 AC: 0 AN: 38426

South Asian (SAS) AF: 0.00 AC: 0 AN: 78402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52580

Middle Eastern (MID) AF: 0.000362 AC: 2 AN: 5522

European-Non Finnish (NFE) AF: 9.14e-7 AC: 1 AN: 1094382

Other (OTH) AF: 0.00 AC: 0 AN: 58102

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Benign	0.65
PhyloP100		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Pathogenic	0.75
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 32
DS_AL_spliceai		0.43		Position offset: 3

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

Other links and lift over

dbSNP: rs377744366; hg19: chr4-56877963;