8-10700373-A-C

Position:

• chr8-10700373-A-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001040032.2(C8orf74):​c.787A>C​(p.Thr263Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 31)
  • Exomes 𝑓: 0.012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: C8orf74 NM_001040032.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0210

Genes affected

C8orf74 (HGNC:32296): (chromosome 8 open reading frame 74)

RP1L1 (HGNC:15946): (RP1 like 1) This gene encodes a member of the doublecortin family. The protein encoded by this gene contains two N-terminal doublecortin domains, which bind microtubules and regulate microtubule polymerization, and two C-terminal large repetitive regions, both of which contain a high percentage of glutamine and glutamic acid residues. This protein is a retinal-specific protein. Its exact length varies among individuals due to the presence of a 16aa repeat in the first C-terminal repetitive region. The 16aa repeat is encoded by the highly polymorphic 48-bp repeat, and 1-6 copies of the 16aa repeat have been identified in normal individuals. The current reference sequence shown here has a single copy of the 16aa repeat. This protein and the RP1 protein, another retinal-specific protein, play essential and synergistic roles in affecting photosensitivity and outer segment morphogenesis of rod photoreceptors. Mutations in this gene cause occult macular dystrophy (OMD). [provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02870369).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C8orf74	NM_001040032.2	c.787A>C	p.Thr263Pro	missense_variant	4/4	ENST00000304519.10
C8orf74	XM_047421493.1	c.844A>C	p.Thr282Pro	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C8orf74	ENST00000304519.10	c.787A>C	p.Thr263Pro	missense_variant	4/4	1	NM_001040032.2	P1
C8orf74	ENST00000523289.5	c.*679A>C		3_prime_UTR_variant, NMD_transcript_variant	5/5	2
RP1L1	ENST00000329335.3	n.231+11584T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 126 AN: 122466 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.00110

Gnomad AMI AF: 0.00258

Gnomad AMR AF: 0.000869

Gnomad ASJ AF: 0.000664

Gnomad EAS AF: 0.000787

Gnomad SAS AF: 0.00115

Gnomad FIN AF: 0.00173

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000908

Gnomad OTH AF: 0.00246

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0119 AC: 7187 AN: 604202 Hom.: 0 Cov.: 25 AF XY: 0.0105 AC XY: 3351 AN XY: 318270

Gnomad4 AFR exome AF: 0.00878

Gnomad4 AMR exome AF: 0.000220

Gnomad4 ASJ exome AF: 0.00331

Gnomad4 EAS exome AF: 0.00302

Gnomad4 SAS exome AF: 0.00266

Gnomad4 FIN exome AF: 0.000786

Gnomad4 NFE exome AF: 0.0164

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00103 AC: 126 AN: 122562 Hom.: 0 Cov.: 31 AF XY: 0.00109 AC XY: 64 AN XY: 58890

Gnomad4 AFR AF: 0.00110

Gnomad4 AMR AF: 0.000867

Gnomad4 ASJ AF: 0.000664

Gnomad4 EAS AF: 0.000787

Gnomad4 SAS AF: 0.00114

Gnomad4 FIN AF: 0.00173

Gnomad4 NFE AF: 0.000908

Gnomad4 OTH AF: 0.00243

Alfa AF: 0.0301 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2021

The c.787A>C (p.T263P) alteration is located in exon 4 (coding exon 4) of the C8orf74 gene. This alteration results from a A to C substitution at nucleotide position 787, causing the threonine (T) at amino acid position 263 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.3
DANN	Benign	0.44
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.090	N
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.0080
Sift	Benign	0.14	T
Sift4G	Benign	0.13	T
Polyphen		0.0020	B
Vest4		0.10
MutPred		0.20		Gain of catalytic residue at P262 (P = 0.0149);
MVP		0.067
MPC		0.019
ClinPred		0.012	T
GERP RS		-2.3
Varity_R		0.13
gMVP		0.076

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

Publications

LitVar

Other links and lift over

dbSNP: rs1175770748; hg19: chr8-10557883;