Genetic Variant NM_001101677.2:c.1123G>T (chr9-135693638-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001101677.2(SOHLH1):c.1123G>T(p.Asp375Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,434,800 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D375N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SOHLH1
NM_001101677.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.816

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOHLH1	NM_001101677.2 link	c.1123G>T	p.Asp375Tyr	missense_variant	Exon 8 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.1123G>T	p.Asp375Tyr	missense_variant	Exon 8 of 8	5	NM_001101677.2	ENSP00000404438.1	Q5JUK2-2
SOHLH1	ENST00000298466.9 link	c.*708G>T		3_prime_UTR_variant	Exon 7 of 7	1		ENSP00000298466.5	Q5JUK2-1
SOHLH1	ENST00000673731.1 link	c.547G>T	p.Asp183Tyr	missense_variant	Exon 5 of 5			ENSP00000501311.1	A0A669KBI8
SOHLH1	ENST00000674066.1 link	n.*22G>T		downstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1434800

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

710936

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32802

American (AMR)

AF:

0.00

AC:

AN:

41360

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25584

East Asian (EAS)

AF:

0.00

AC:

AN:

38018

South Asian (SAS)

AF:

0.0000245

AC:

AN:

81796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51160

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099020

Other (OTH)

AF:

0.00

AC:

AN:

59404

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.57

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.46

MetaSVM

Benign

-0.69

PhyloP100

0.82

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.19

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.42

MutPred

0.42

Loss of ubiquitination at K374 (P = 0.1121);

MVP

0.52

MPC

0.28

ClinPred

0.93

GERP RS

5.3

gMVP

0.21

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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NM_001101677.2:c.1123G>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over