rs864309645

Variant names:

• chr9-135695219-TA-T
• rs864309645
• NM_001101677.2:c.705delT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001101677.2(SOHLH1):​c.705delT​(p.Lys236ArgfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: SOHLH1 NM_001101677.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.0800
• 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 12 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 9-135695219-TA-T is Pathogenic according to our data. Variant chr9-135695219-TA-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 218901.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOHLH1	NM_001101677.2	c.705delT	p.Lys236ArgfsTer3	frameshift_variant	Exon 6 of 8	ENST00000425225.2	NP_001095147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOHLH1	ENST00000425225.2	c.705delT	p.Lys236ArgfsTer3	frameshift_variant	Exon 6 of 8	5	NM_001101677.2	ENSP00000404438.1
SOHLH1	ENST00000298466.9	c.705delT	p.Lys236ArgfsTer3	frameshift_variant	Exon 6 of 7	1		ENSP00000298466.5
SOHLH1	ENST00000673731.1	c.63delT	p.Lys22ArgfsTer3	frameshift_variant	Exon 2 of 5			ENSP00000501311.1
SOHLH1	ENST00000674066.1	n.2295delT		non_coding_transcript_exon_variant	Exon 9 of 11

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ovarian dysgenesis 5 Pathogenic:1

May 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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 v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.080
Mutation Taster		=55/145	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs864309645; hg19: chr9-138587065;