rs376553815

Variant names:

• chr4-55991942-C-A
• rs376553815
• NM_025009.5:c.1866C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-55991942-C-A
• chr4-55991942-C-G
• chr4-55991942-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025009.5(CEP135):​c.1866C>A​(p.Ser622Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000038 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CEP135 NM_025009.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.695
• 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

ENSG00000299857 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03604892).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP135	NM_025009.5	c.1866C>A	p.Ser622Arg	missense_variant	Exon 15 of 26	ENST00000257287.5	NP_079285.2
CEP135	XM_006714055.4	c.1833C>A	p.Ser611Arg	missense_variant	Exon 15 of 26		XP_006714118.1
CEP135	XM_005265788.5	c.795C>A	p.Ser265Arg	missense_variant	Exon 8 of 19		XP_005265845.1
CEP135	XM_011534412.2	c.336C>A	p.Ser112Arg	missense_variant	Exon 5 of 16		XP_011532714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP135	ENST00000257287.5	c.1866C>A	p.Ser622Arg	missense_variant	Exon 15 of 26	1	NM_025009.5	ENSP00000257287.3
CEP135	ENST00000506202.1	n.1816C>A		non_coding_transcript_exon_variant	Exon 8 of 19	1
ENSG00000299857	ENST00000766957.1	n.107+5510G>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000383 AC: 5 AN: 1305468 Hom.: 0 Cov.: 25 AF XY: 0.00000306 AC XY: 2 AN XY: 652944

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

African (AFR) AF: 0.00 AC: 0 AN: 27554

American (AMR) AF: 0.00 AC: 0 AN: 29842

Ashkenazi Jewish (ASJ) AF: 0.0000428 AC: 1 AN: 23368

East Asian (EAS) AF: 0.00 AC: 0 AN: 36890

South Asian (SAS) AF: 0.0000137 AC: 1 AN: 72824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4586

European-Non Finnish (NFE) AF: 0.00000299 AC: 3 AN: 1003940

Other (OTH) AF: 0.00 AC: 0 AN: 54230

⚠️ 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.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.37
DANN	Benign	0.85
DEOGEN2	Benign	0.0042	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.86	L
PhyloP100		-0.69
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.063
Sift	Benign	0.61	T
Sift4G	Benign	0.58	T
Polyphen		0.0020	B
Vest4		0.17
MutPred		0.15		Loss of ubiquitination at K624 (P = 0.1);
MVP		0.14
MPC		0.072
ClinPred		0.038	T
GERP RS		-4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.060
gMVP		0.066
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs376553815; hg19: chr4-56858108;