Genetic Variant NM_001101677.2:c.824C>A (chr9-135695101-G-T) – 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.824C>A(p.Ala275Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,192 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A275G) has been classified as Uncertain significance.

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: -0.270

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):

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

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=0.040161997).

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.824C>A	p.Ala275Glu	missense	Exon 6 of 8	NP_001095147.2	Q5JUK2-2
	SOHLH1	NM_001012415.3		c.824C>A	p.Ala275Glu	missense	Exon 6 of 7	NP_001012415.3	Q5JUK2-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SOHLH1	ENST00000425225.2	TSL:5 MANE Select	c.824C>A	p.Ala275Glu	missense	Exon 6 of 8	ENSP00000404438.1	Q5JUK2-2
SOHLH1	ENST00000298466.9	TSL:1	c.824C>A	p.Ala275Glu	missense	Exon 6 of 7	ENSP00000298466.5	Q5JUK2-1
SOHLH1	ENST00000950496.1		c.824C>A	p.Ala275Glu	missense	Exon 8 of 10	ENSP00000620555.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446192

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33144

American (AMR)

AF:

0.0000231

AC:

AN:

43226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25740

East Asian (EAS)

AF:

0.00

AC:

AN:

39050

South Asian (SAS)

AF:

0.00

AC:

AN:

83844

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4254

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106932

Other (OTH)

AF:

0.00

AC:

AN:

59648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.29

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.044

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0089

LIST_S2

Benign

0.30

M_CAP

Benign

0.0046

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.90

PhyloP100

-0.27

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.57

REVEL

Benign

0.029

Sift

Benign

0.68

Sift4G

Benign

0.84

Polyphen

0.0010

Vest4

0.055

MutPred

0.14

Loss of glycosylation at P280 (P = 0.3066)

MVP

0.088

MPC

0.046

ClinPred

0.016

GERP RS

-0.27

Varity_R

0.058

gMVP

0.029

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over