rs115408010

Variant names:

• chr4-55953268-C-T
• rs115408010
• NM_025009.5:c.297C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-55953268-C-T
• chr4-55953268-C-A
• chr4-55953268-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_025009.5(CEP135):​c.297C>T​(p.His99His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000865 in 1,508,172 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (4 hom.)
• Consequence: CEP135 NM_025009.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.23
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 4-55953268-C-T is Benign according to our data. Variant chr4-55953268-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00294 (448/152170) while in subpopulation AFR AF = 0.00913 (379/41532). AF 95% confidence interval is 0.00837. There are 1 homozygotes in GnomAd4. There are 213 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025009.5. 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
	CEP135	NM_025009.5	MANE Select	c.297C>T	p.His99His	synonymous	Exon 3 of 26	NP_079285.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP135	ENST00000257287.5	TSL:1 MANE Select	c.297C>T	p.His99His	synonymous	Exon 3 of 26	ENSP00000257287.3	Q66GS9-1
	CEP135	ENST00000916105.1		c.297C>T	p.His99His	synonymous	Exon 3 of 27	ENSP00000586164.1
	CEP135	ENST00000916104.1		c.297C>T	p.His99His	synonymous	Exon 3 of 26	ENSP00000586163.1

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 448 AN: 152052 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00915

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00115 AC: 207 AN: 180528 AF XY: 0.000946

Gnomad AFR exome AF: 0.00971

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.000168

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000397

Gnomad OTH exome AF: 0.00337

GnomAD4 exome AF: 0.000631 AC: 856 AN: 1356002 Hom.: 4 Cov.: 26 AF XY: 0.000608 AC XY: 407 AN XY: 668926

African (AFR) AF: 0.0110 AC: 310 AN: 28066

American (AMR) AF: 0.00193 AC: 49 AN: 25362

Ashkenazi Jewish (ASJ) AF: 0.000410 AC: 9 AN: 21968

East Asian (EAS) AF: 0.00 AC: 0 AN: 35354

South Asian (SAS) AF: 0.0000418 AC: 3 AN: 71834

European-Finnish (FIN) AF: 0.0000197 AC: 1 AN: 50864

Middle Eastern (MID) AF: 0.00493 AC: 23 AN: 4668

European-Non Finnish (NFE) AF: 0.000361 AC: 384 AN: 1062368

Other (OTH) AF: 0.00139 AC: 77 AN: 55518

GnomAD4 genome AF: 0.00294 AC: 448 AN: 152170 Hom.: 1 Cov.: 33 AF XY: 0.00286 AC XY: 213 AN XY: 74396

African (AFR) AF: 0.00913 AC: 379 AN: 41532

American (AMR) AF: 0.00137 AC: 21 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68010

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00150 Hom.: 2

Bravo AF: 0.00369

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	CEP135-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.62
DANN	Benign	0.37
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs115408010; hg19: chr4-56819434;