6-118481910-A-AT

Variant names:

• chr6-118481910-A-AT
• rs1554203314
• NM_001042475.3:c.1613dupA

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PVS1 BS2_Supporting

The NM_001042475.3(CEP85L):​c.1613dupA​(p.Asn538LysfsTer2) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000384 in 1,563,058 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CEP85L NM_001042475.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12

Genes affected

CEP85L (HGNC:21638): (centrosomal protein 85 like) The protein encoded by this gene was identified as a breast cancer antigen. Nothing more is known of its function at this time. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

LOC105377971 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP85L	NM_001042475.3	c.1613dupA	p.Asn538LysfsTer2	frameshift_variant	Exon 8 of 13	ENST00000368491.8	NP_001035940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP85L	ENST00000368491.8	c.1613dupA	p.Asn538LysfsTer2	frameshift_variant	Exon 8 of 13	1	NM_001042475.3	ENSP00000357477.3
CEP85L	ENST00000434604.5	c.1622dupA	p.Asn541LysfsTer2	frameshift_variant	Exon 9 of 9	1		ENSP00000392131.1
CEP85L	ENST00000368488.9	c.1622dupA	p.Asn541LysfsTer2	frameshift_variant	Exon 9 of 14	5		ENSP00000357474.5

Frequencies

GnomAD3 genomes AF: 0.00000666 AC: 1 AN: 150204 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome AF: 0.00000354 AC: 5 AN: 1412854 Hom.: 0 Cov.: 28 AF XY: 0.00000142 AC XY: 1 AN XY: 701944

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000525

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000276

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000666 AC: 1 AN: 150204 Hom.: 0 Cov.: 31 AF XY: 0.0000137 AC XY: 1 AN XY: 73200

Gnomad4 AFR AF: 0.0000245

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 16, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554203314; hg19: chr6-118803073;