14-88385821-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_018418.5(SPATA7):c.3G>T(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000237 in 1,606,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: SPATA7 NM_018418.5 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.71

Genes affected

SPATA7 (HGNC:20423): (spermatogenesis associated 7) This gene, originally isolated from testis, is also expressed in retina. Mutations in this gene are associated with Leber congenital amaurosis and juvenile retinitis pigmentosa. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_018418.5 (SPATA7) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 844972
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-88385821-G-T is Pathogenic according to our data. Variant chr14-88385821-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1704585.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-88385821-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPATA7	NM_018418.5	c.3G>T	p.Met1?	start_lost	1/12	ENST00000393545.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPATA7	ENST00000393545.9	c.3G>T	p.Met1?	start_lost	1/12	1	NM_018418.5	P2

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152214 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000723

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000855 AC: 2 AN: 233902 Hom.: 0 AF XY: 0.00000789 AC XY: 1 AN XY: 126780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000515

Gnomad NFE exome AF: 0.00000953

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000227 AC: 33 AN: 1454458 Hom.: 0 Cov.: 31 AF XY: 0.0000235 AC XY: 17 AN XY: 722734

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000298

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152214 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74364

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 05, 2022

Variant summary: SPATA7 c.3G>T (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (Met 52) is located in exon 3 of the encoded protein. An activation of potential downstream translation initiation site would result in a truncated protein. At-least two other presumably pathogenic truncating variants have been reported upstream of this alternate codon in the HGMD database (example, c.20_21delTC, p.Val7Glufs*16). The variant allele was found at a frequency of 8.6e-06 in 233902 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3G>T has been reported in the literature in at-least one individual affected with Leber Congenital Amaurosis in whom a second variant was not identified (example, Perrault_2010). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	26
Dann	Uncertain	0.98
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-1.1	N;N;N;N;N;N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Benign	0.19	T;T;T;.;T;T
Polyphen		1.0	D;B;D;.;.;.
Vest4		0.91
MutPred		1.0		Loss of methylation at R6 (P = 0.066);Loss of methylation at R6 (P = 0.066);Loss of methylation at R6 (P = 0.066);Loss of methylation at R6 (P = 0.066);Loss of methylation at R6 (P = 0.066);Loss of methylation at R6 (P = 0.066);
MVP		0.040
ClinPred		0.94	D
GERP RS		4.3
Varity_R		0.94
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200244203; hg19: chr14-88852165;