9-135693638-C-T

Variant names:

• chr9-135693638-C-T
• rs779431706
• NM_001101677.2:c.1123G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001101677.2(SOHLH1):​c.1123G>A​(p.Asp375Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,587,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: SOHLH1 NM_001101677.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.816
• 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):

• ovarian dysgenesis 5

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

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27396607).

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.1123G>A	p.Asp375Asn	missense	Exon 8 of 8	NP_001095147.2	Q5JUK2-2
	SOHLH1	NM_001012415.3		c.*708G>A		3_prime_UTR	Exon 7 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.1123G>A	p.Asp375Asn	missense	Exon 8 of 8	ENSP00000404438.1	Q5JUK2-2
	SOHLH1	ENST00000298466.9	TSL:1	c.*708G>A		3_prime_UTR	Exon 7 of 7	ENSP00000298466.5	Q5JUK2-1
	SOHLH1	ENST00000950496.1		c.1123G>A	p.Asp375Asn	missense	Exon 10 of 10	ENSP00000620555.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000436 AC: 9 AN: 206266 AF XY: 0.0000359

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.000951

GnomAD4 exome AF: 0.0000105 AC: 15 AN: 1434800 Hom.: 0 Cov.: 29 AF XY: 0.00000985 AC XY: 7 AN XY: 710936

African (AFR) AF: 0.00 AC: 0 AN: 32802

American (AMR) AF: 0.00 AC: 0 AN: 41360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25584

East Asian (EAS) AF: 0.00 AC: 0 AN: 38018

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51160

Middle Eastern (MID) AF: 0.00212 AC: 12 AN: 5656

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099020

Other (OTH) AF: 0.0000337 AC: 2 AN: 59404

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000249 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.79	T
PhyloP100		0.82
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.22
MutPred		0.37		Gain of ubiquitination at K374 (P = 0.0978)
MVP		0.57
MPC		0.23
ClinPred		0.32	T
GERP RS		5.3
gMVP		0.065
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs779431706; hg19: chr9-138585484;