Genetic Variant NM_001101677.2:c.962G>T (chr9-135693799-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001101677.2(SOHLH1):c.962G>T(p.Arg321Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000281 in 1,422,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 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. R321Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

SOHLH1
NM_001101677.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.271

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3274719).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOHLH1	NM_001101677.2 link	c.962G>T	p.Arg321Leu	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.962G>T	p.Arg321Leu	missense_variant	Exon 8 of 8	5	NM_001101677.2	ENSP00000404438.1	Q5JUK2-2
SOHLH1	ENST00000298466.9 link	c.*547G>T		3_prime_UTR_variant	Exon 7 of 7	1		ENSP00000298466.5	Q5JUK2-1
SOHLH1	ENST00000673731.1 link	c.386G>T	p.Arg129Leu	missense_variant	Exon 5 of 5			ENSP00000501311.1	A0A669KBI8
SOHLH1	ENST00000674066.1 link	n.2552G>T		non_coding_transcript_exon_variant	Exon 11 of 11

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000281

AC:

AN:

1422206

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

703316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32432

American (AMR)

AF:

0.00

AC:

AN:

39958

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25458

East Asian (EAS)

AF:

0.00

AC:

AN:

37230

South Asian (SAS)

AF:

0.00

AC:

AN:

80894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49758

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00000366

AC:

AN:

1091834

Other (OTH)

AF:

0.00

AC:

AN:

58908

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

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.97

Eigen

Benign

0.00015

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.52

M_CAP

Benign

0.028

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.96

PhyloP100

0.27

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.098

Sift

Pathogenic

0.0

Sift4G

Benign

0.11

Polyphen

1.0

Vest4

0.36

MutPred

0.28

Loss of methylation at R321 (P = 0.0055);

MVP

0.50

MPC

0.041

ClinPred

0.41

GERP RS

1.4

gMVP

0.13

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.962G>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