rs140132974

Positions:

chr9-135697628-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_StrongBS2

The NM_001101677.2(SOHLH1):c.346-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,610,880 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 18 hom. )

Consequence

SOHLH1
NM_001101677.2 splice_acceptor, intron

Scores

Splicing: ADA: 0.9998

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:1

Conservation

PhyloP100: 0.449

Variant links:

Genes affected

SOHLH1 (HGNC:27845): (spermatogenesis and oogenesis specific basic helix-loop-helix 1) This gene encodes one of testis-specific transcription factors which are essential for spermatogenesis, oogenesis and folliculogenesis. This gene is located on chromosome 9. Mutations in this gene are associated with nonobstructive azoospermia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2013]

SOHLH1 links:

SOHLH1 (HGNC:):

SOHLH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.103951894 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.9, offset of 18, new splice context is: aaattcttgcttcctccaAGgaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

BS2

High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOHLH1	NM_001101677.2 linkuse as main transcript	c.346-1G>A		splice_acceptor_variant, intron_variant		ENST00000425225.2	NP_001095147.2	Q5JUK2-2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
SOHLH1	ENST00000425225.2 linkuse as main transcript	c.346-1G>A	splice_acceptor_variant, intron_variant	5	NM_001101677.2	ENSP00000404438.1	Q5JUK2-2
SOHLH1	ENST00000298466.9 linkuse as main transcript	c.346-1G>A	splice_acceptor_variant, intron_variant	1		ENSP00000298466.5	Q5JUK2-1
SOHLH1	ENST00000674066.1 linkuse as main transcript	n.1936-1G>A	splice_acceptor_variant, intron_variant

Frequencies

GnomAD3 genomes

AF:

0.00182

AC:

277

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0102

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00290

AC:

723

AN:

249600

Hom.:

AF XY:

0.00275

AC XY:

373

AN XY:

135504

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00975

Gnomad SAS exome

AF:

0.000882

Gnomad FIN exome

AF:

0.0149

Gnomad NFE exome

AF:

0.00154

Gnomad OTH exome

AF:

0.00361

GnomAD4 exome

AF:

0.00128

AC:

1860

AN:

1458528

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

953

AN XY:

725514

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000896

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0102

Gnomad4 SAS exome

AF:

0.000906

Gnomad4 FIN exome

AF:

0.0149

Gnomad4 NFE exome

AF:

0.000424

Gnomad4 OTH exome

AF:

0.00212

GnomAD4 genome

AF:

0.00181

AC:

275

AN:

152352

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

181

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0102

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0151

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00113

Hom.:

Bravo

AF:

0.000684

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00321

AC:

390

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Spermatogenic Failure

Pathogenic:1

Pathogenic, no assertion criteria provided

curation

Reproductive Health Research and Development, BGI Genomics

Jan 06, 2020

NG_033784.1(NM_001101677.1):c.346-1G>A in the SOHLH1 gene has an allele frequency of 0.015 in European (Finnish) subpopulation in the gnomAD database. 5 homozygous occurrences are observed in the gnomAD database. This variant destroys the canonical splice donor site. It is was predicted to lead to skipping of exon 4 or activation of a cryptic splice acceptor site in exon 4. The c.346-1G>A has been detected in two individuals with non-obstructive azoospermia (PMID: 20506135, 28718531). In the patient reported by Nakamura (PMID: 20506135), c.346-1G>A mutation was not detected in both parents of each probands, indicating a de novo event. We interpret it as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1, PS2, PP4, BS1. -

Spermatogenic failure 32

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 11, 2018

- -

Ovarian dysgenesis 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

PVS1_Strong+BS1 -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.74

CADD

Benign

DANN

Benign

0.81

Eigen

Benign

0.12

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.11

GERP RS

3.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.75

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.84

Position offset: -19

DS_AL_spliceai

0.99

Position offset: -1

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