9-135699441-G-C

Variant names:

• chr9-135699441-G-C
• rs864309646
• NM_001101677.2:c.27C>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001101677.2(SOHLH1):​c.27C>G​(p.Tyr9*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 35)
• Consequence: SOHLH1 NM_001101677.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -2.97
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• ovarian dysgenesis 5

  Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypogonadism

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-135699441-G-C is Pathogenic according to our data. Variant chr9-135699441-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 218902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101677.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOHLH1	NM_001101677.2	MANE Select	c.27C>G	p.Tyr9*	stop_gained	Exon 1 of 8	NP_001095147.2
	SOHLH1	NM_001012415.3		c.27C>G	p.Tyr9*	stop_gained	Exon 1 of 7	NP_001012415.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOHLH1	ENST00000425225.2	TSL:5 MANE Select	c.27C>G	p.Tyr9*	stop_gained	Exon 1 of 8	ENSP00000404438.1
	SOHLH1	ENST00000298466.9	TSL:1	c.27C>G	p.Tyr9*	stop_gained	Exon 1 of 7	ENSP00000298466.5
	SOHLH1	ENST00000674066.1		n.1217-315C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 35

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ovarian dysgenesis 5 Pathogenic:2

May 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Apr 16, 2018

SIB Swiss Institute of Bioinformatics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Pathogenic, for Ovarian dysgenesis 5, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PVS1 => Predicted nullvariant in a gene where LOF is a known mechanism of disease (PMID:25774885). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:25774885).

Nonsyndromic hypergonadotropic hypogonadism Pathogenic:1

May 01, 2015

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Benign	0.96
Eigen	Benign	-0.57
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.016	N
PhyloP100		-3.0
Vest4		0.30
GERP RS		-2.4
PromoterAI		-0.017	Neutral
Mutation Taster		=48/152	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs864309646; hg19: chr9-138591287;