9-135693781-G-C

Variant names:

• chr9-135693781-G-C
• rs781344496
• NM_001101677.2:c.980C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001101677.2(SOHLH1):​c.980C>G​(p.Ala327Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A327V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SOHLH1 NM_001101677.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.240
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052150965).

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.980C>G	p.Ala327Gly	missense	Exon 8 of 8	NP_001095147.2	Q5JUK2-2
	SOHLH1	NM_001012415.3		c.*565C>G		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.980C>G	p.Ala327Gly	missense	Exon 8 of 8	ENSP00000404438.1	Q5JUK2-2
	SOHLH1	ENST00000298466.9	TSL:1	c.*565C>G		3_prime_UTR	Exon 7 of 7	ENSP00000298466.5	Q5JUK2-1
	SOHLH1	ENST00000950496.1		c.980C>G	p.Ala327Gly	missense	Exon 10 of 10	ENSP00000620555.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428730 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 707472

African (AFR) AF: 0.0000307 AC: 1 AN: 32598

American (AMR) AF: 0.00 AC: 0 AN: 40734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25518

East Asian (EAS) AF: 0.00 AC: 0 AN: 37556

South Asian (SAS) AF: 0.00 AC: 0 AN: 81268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096028

Other (OTH) AF: 0.00 AC: 0 AN: 59198

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.2
DANN	Benign	0.43
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.24
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.059
Sift	Benign	0.076	T
Sift4G	Benign	0.28	T
Polyphen		0.19	B
Vest4		0.087
MutPred		0.063		Loss of catalytic residue at A327 (P = 0.1042)
MVP		0.072
MPC		0.040
ClinPred		0.057	T
GERP RS		-0.38
gMVP		0.014
Mutation Taster		=100/0	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: rs781344496; hg19: chr9-138585627;