dbSNP rs1004968910: SHOC1:p.Arg592* (chr9-111727693-G-A) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001378211.1(SHOC1):c.1774C>T(p.Arg592*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000872 in 1,606,286 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 (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

SHOC1
NM_001378211.1 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 0.293

Variant links:

Genes affected

SHOC1 (HGNC:26535): (shortage in chiasmata 1) Enables single-stranded DNA binding activity. Predicted to be involved in resolution of meiotic recombination intermediates. Predicted to be located in chromosome. Predicted to be active in condensed nuclear chromosome. [provided by Alliance of Genome Resources, Apr 2022]

SHOC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-111727693-G-A is Pathogenic according to our data. Variant chr9-111727693-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1693564.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOC1	NM_001378211.1 link	c.1774C>T	p.Arg592*	stop_gained	Exon 13 of 28	ENST00000682961.1	NP_001365140.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOC1	ENST00000682961.1 link	c.1774C>T	p.Arg592*	stop_gained	Exon 13 of 28		NM_001378211.1	ENSP00000508388.1		A0A804HLJ8

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151938

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

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

GnomAD2 exomes

AF:

0.0000123

AC:

AN:

244332

AF XY:

0.00000758

show subpopulations

Gnomad AFR exome

AF:

0.0000620

Gnomad AMR exome

AF:

0.0000304

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000897

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000688

AC:

AN:

1454348

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723112

show subpopulations

African (AFR)

AF:

0.0000303

AC:

AN:

32968

American (AMR)

AF:

0.0000232

AC:

AN:

43040

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25844

East Asian (EAS)

AF:

0.00

AC:

AN:

39532

South Asian (SAS)

AF:

0.00

AC:

AN:

84148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00000721

AC:

AN:

1109704

Other (OTH)

AF:

0.00

AC:

AN:

60124

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151938

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74160

show subpopulations

African (AFR)

AF:

0.0000967

AC:

AN:

41382

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67966

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.588

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

SHOC1-related condition

Pathogenic:1

Mar 04, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SHOC1 c.1582C>T variant is predicted to result in premature protein termination (p.Arg528*). This variant was reported in the compound heterozygous state with a second premature termination variant in two siblings with azoospermia (Yao et al. 2021. PubMed ID: 32900840). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. Nonsense variants in SHOC1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Spermatogenic failure 75

Pathogenic:1

Jul 06, 2022

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.0088

FATHMM_MKL

Benign

0.34

PhyloP100

0.29

Vest4

0.35

GERP RS

-2.4

Mutation Taster

=40/160

disease causing (fs/PTC)

(source)

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

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rs1004968910

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over