4-55952272-T-G

Variant names:

• chr4-55952272-T-G
• rs75376349
• NM_025009.5:c.113+29T>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_025009.5(CEP135):​c.113+29T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000407 in 1,284,074 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: CEP135 NM_025009.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.98
• 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

LOC124900705 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 4-55952272-T-G is Benign according to our data. Variant chr4-55952272-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 1254843.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00206 (314/152340) while in subpopulation AFR AF = 0.00731 (304/41586). AF 95% confidence interval is 0.00663. There are 1 homozygotes in GnomAd4. There are 166 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP135	NM_025009.5	c.113+29T>G		intron_variant	Intron 2 of 25	ENST00000257287.5	NP_079285.2
CEP135	XM_006714055.4	c.113+29T>G		intron_variant	Intron 2 of 25		XP_006714118.1
LOC124900705	XR_007058124.1	n.*119A>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP135	ENST00000257287.5	c.113+29T>G		intron_variant	Intron 2 of 25	1	NM_025009.5	ENSP00000257287.3
CEP135	ENST00000506809.1	n.302T>G		non_coding_transcript_exon_variant	Exon 2 of 2	3
CEP135	ENST00000422247.6	c.113+29T>G		intron_variant	Intron 2 of 5	2		ENSP00000412799.2
CEP135	ENST00000706800.1	n.286+29T>G		intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 314 AN: 152222 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00733

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.000414 AC: 101 AN: 243680 AF XY: 0.000265

Gnomad AFR exome AF: 0.00602

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000185 AC: 209 AN: 1131734 Hom.: 0 Cov.: 15 AF XY: 0.000130 AC XY: 75 AN XY: 578804

African (AFR) AF: 0.00688 AC: 184 AN: 26746

American (AMR) AF: 0.000115 AC: 5 AN: 43322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23922

East Asian (EAS) AF: 0.00 AC: 0 AN: 38066

South Asian (SAS) AF: 0.0000378 AC: 3 AN: 79308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53060

Middle Eastern (MID) AF: 0.000195 AC: 1 AN: 5138

European-Non Finnish (NFE) AF: 0.00000123 AC: 1 AN: 812832

Other (OTH) AF: 0.000304 AC: 15 AN: 49340

GnomAD4 genome AF: 0.00206 AC: 314 AN: 152340 Hom.: 1 Cov.: 33 AF XY: 0.00223 AC XY: 166 AN XY: 74496

African (AFR) AF: 0.00731 AC: 304 AN: 41586

American (AMR) AF: 0.000654 AC: 10 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000684 Hom.: 0

Bravo AF: 0.00204

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 27, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.0020
DANN	Benign	0.33
PhyloP100		-3.0

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: rs75376349; hg19: chr4-56818438;