Genetic Variant SOHLH1:p.Gly258Arg (chr9-135695153-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001101677.2(SOHLH1):c.772G>C(p.Gly258Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SOHLH1
NM_001101677.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0440

Publications

0 publications found

Variant links:

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

SOHLH1 links:

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ACMG classification

Classification was made for transcript

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=0.03605205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOHLH1	NM_001101677.2 link	c.772G>C	p.Gly258Arg	missense_variant	Exon 6 of 8	ENST00000425225.2	NP_001095147.2	Q5JUK2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SOHLH1	ENST00000425225.2 link	c.772G>C	p.Gly258Arg	missense_variant	Exon 6 of 8	5	NM_001101677.2	ENSP00000404438.1	Q5JUK2-2
SOHLH1	ENST00000298466.9 link	c.772G>C	p.Gly258Arg	missense_variant	Exon 6 of 7	1		ENSP00000298466.5	Q5JUK2-1
SOHLH1	ENST00000673731.1 link	c.130G>C	p.Gly44Arg	missense_variant	Exon 2 of 5			ENSP00000501311.1	A0A669KBI8
SOHLH1	ENST00000674066.1 link	n.2362G>C		non_coding_transcript_exon_variant	Exon 9 of 11

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1448266

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719272

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33314

American (AMR)

AF:

0.0000233

AC:

AN:

42952

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25718

East Asian (EAS)

AF:

0.00

AC:

AN:

39172

South Asian (SAS)

AF:

0.00

AC:

AN:

83832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4946

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107480

Other (OTH)

AF:

0.00

AC:

AN:

59832

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

7.9

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.076

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0080

LIST_S2

Benign

0.37

T;T

M_CAP

Benign

0.0044

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;L

PhyloP100

-0.044

PrimateAI

Benign

0.31

PROVEAN

Benign

0.28

N;N

REVEL

Benign

0.0060

Sift

Benign

0.18

T;T

Sift4G

Benign

0.31

T;T

Polyphen

0.0

B;B

Vest4

0.11

MutPred

0.14

Loss of glycosylation at S257 (P = 0.0545);Loss of glycosylation at S257 (P = 0.0545);

MVP

0.10

MPC

0.040

ClinPred

0.062

GERP RS

-0.74

Varity_R

0.041

gMVP

0.036

Mutation Taster

=96/4

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over