Genetic Variant NM_018418.5:c.220G>C (chr14-88396185-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018418.5(SPATA7):c.220G>C(p.Val74Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,812 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V74M) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SPATA7
NM_018418.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.07

Publications

47 publications found

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 Gene-Disease associations (from GenCC):

Leber congenital amaurosis 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
severe early-childhood-onset retinal dystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SPATA7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.055698305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPATA7	NM_018418.5 link	c.220G>C	p.Val74Leu	missense_variant	Exon 4 of 12	ENST00000393545.9	NP_060888.2	Q9P0W8-1V9HVY9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPATA7	ENST00000393545.9 link	c.220G>C	p.Val74Leu	missense_variant	Exon 4 of 12	1	NM_018418.5	ENSP00000377176.4		Q9P0W8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250882

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1456812

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724938

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33274

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00

AC:

AN:

86100

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4656

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108870

Other (OTH)

AF:

0.00

AC:

AN:

60100

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.0040

.;T;.;T;T;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.17

.;T;T;T;T;T

M_CAP

Benign

0.0050

MetaRNN

Benign

0.056

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

.;N;.;.;.;N

PhyloP100

1.1

PrimateAI

Benign

0.35

PROVEAN

Benign

0.33

N;N;N;N;N;N

REVEL

Benign

0.038

Sift

Benign

0.24

T;T;T;T;T;T

Sift4G

Benign

0.32

T;T;T;T;T;T

Polyphen

0.0010

B;B;B;.;.;.

Vest4

0.11

MutPred

0.22

.;Loss of catalytic residue at V74 (P = 0.028);.;.;.;Loss of catalytic residue at V74 (P = 0.028);

MVP

0.048

MPC

0.093

ClinPred

0.045

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.041

gMVP

0.033

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over