NM_001101677.2:c.760C>T

Variant names:

• chr9-135695165-G-A
• NM_001101677.2:c.760C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001101677.2(SOHLH1):​c.760C>T​(p.Pro254Ser) variant causes a missense 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SOHLH1 NM_001101677.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.367
• Publications: 0 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):

• spermatogenic failure 32

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• ovarian dysgenesis 5

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

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13564363).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOHLH1	NM_001101677.2	MANE Select	c.760C>T	p.Pro254Ser	missense	Exon 6 of 8	NP_001095147.2	Q5JUK2-2
	SOHLH1	NM_001012415.3		c.760C>T	p.Pro254Ser	missense	Exon 6 of 7	NP_001012415.3	Q5JUK2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOHLH1	ENST00000425225.2	TSL:5 MANE Select	c.760C>T	p.Pro254Ser	missense	Exon 6 of 8	ENSP00000404438.1	Q5JUK2-2
	SOHLH1	ENST00000298466.9	TSL:1	c.760C>T	p.Pro254Ser	missense	Exon 6 of 7	ENSP00000298466.5	Q5JUK2-1
	SOHLH1	ENST00000950496.1		c.760C>T	p.Pro254Ser	missense	Exon 8 of 10	ENSP00000620555.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450704 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 720662

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 43276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25770

East Asian (EAS) AF: 0.00 AC: 0 AN: 39348

South Asian (SAS) AF: 0.00 AC: 0 AN: 84102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5110

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108566

Other (OTH) AF: 0.00 AC: 0 AN: 59912

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Ovarian dysgenesis 5;C4748253:Spermatogenic failure 32 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.37
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.047
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.028	D
Polyphen		0.80	P
Vest4		0.19
MutPred		0.28		Gain of sheet (P = 0.0036)
MVP		0.59
MPC		0.24
ClinPred		0.70	D
GERP RS		1.4
Varity_R		0.084
gMVP		0.16
Mutation Taster		=98/2	polymorphism

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

hg19: chr9-138587011;