14-88385821-G-A

Position:

chr14-88385821-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PS1_ModeratePM2PP5

The NM_018418.5(SPATA7):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000822 in 1,606,674 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

SPATA7
NM_018418.5 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 3.71

Variant links:

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]

SPATA7 links:

SPATA7 (HGNC:):

SPATA7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_018418.5 (SPATA7) was described as [Likely_pathogenic] in Lovd

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-88385821-G-A is Pathogenic according to our data. Variant chr14-88385821-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 844972.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}. Variant chr14-88385821-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPATA7	NM_018418.5 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	1/12	ENST00000393545.9	NP_060888.2	Q9P0W8-1V9HVY9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPATA7	ENST00000393545.9 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	1/12	1	NM_018418.5	ENSP00000377176.4		Q9P0W8-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000470

AC:

AN:

233902

Hom.:

AF XY:

0.0000631

AC XY:

AN XY:

126780

show subpopulations

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:

0.00

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000859

AC:

125

AN:

1454458

Hom.:

Cov.:

AF XY:

0.0000927

AC XY:

AN XY:

722734

show subpopulations

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:

0.000105

Gnomad4 OTH exome

AF:

0.000150

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000654

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000413

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Leber congenital amaurosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Oct 17, 2024

Variant summary: SPATA7 c.3G>A (p.Met1Ile) 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 (Met52) is located in exon 3 of the encoded protein. An activation of potential downstream translation initiation at this site would result in a shortened protein missing the first 51 amino acids from the protein sequence. Other presumably pathogenic truncating variants have been reported upstream of this alternate initiation codon in the HGMD or internal database (example, c.20_21delTC, p.Val7Glufs*16, c.136C>T, p.Gln46X). The variant allele was found at a frequency of 4.7e-05 in 233902 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SPATA7 causing Leber Congenital Amaurosis (4.7e-05 vs 0.00087), allowing no conclusion about variant significance. c.3G>A has been reported in the literature in at least two compound heterozygous individuals affected with retinitis pigmentosa (e.g., Neveling_2012, Weisschuh_2024). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24265693, 22334370, 37734845). ClinVar contains an entry for this variant (Variation ID: 844972). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Leber congenital amaurosis 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2022

This sequence change affects the initiator methionine of the SPATA7 mRNA. The next in-frame methionine is located at codon 52. This variant is present in population databases (rs200244203, gnomAD 0.01%). Disruption of the initiator codon has been observed in individual(s) with retinitis pigmentosa (PMID: 22334370). ClinVar contains an entry for this variant (Variation ID: 844972). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.015

.;T;.;T;T;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.90

.;D;D;D;D;D

M_CAP

Pathogenic

0.72

MetaRNN

Uncertain

0.49

T;T;T;T;T;T

MetaSVM

Benign

-0.59

PROVEAN

Benign

-1.1

N;N;N;N;N;N

REVEL

Benign

0.28

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

0.99

GERP RS

4.3

Varity_R

0.94

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over