9-135694417-G-T

Position:

• chr9-135694417-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001101677.2(SOHLH1):​c.916C>A​(p.Leu306Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,613,312 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (36 hom.)
• Consequence: SOHLH1 NM_001101677.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.11

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00800392).
• BP6: Variant 9-135694417-G-T is Benign according to our data. Variant chr9-135694417-G-T is described in ClinVar as [Benign]. Clinvar id is 772940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOHLH1	NM_001101677.2	c.916C>A	p.Leu306Met	missense_variant	7/8	ENST00000425225.2	NP_001095147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOHLH1	ENST00000425225.2	c.916C>A	p.Leu306Met	missense_variant	7/8	5	NM_001101677.2	ENSP00000404438.1
SOHLH1	ENST00000298466.9	c.916C>A	p.Leu306Met	missense_variant	7/7	1		ENSP00000298466.5
SOHLH1	ENST00000673731.1	c.274C>A	p.Leu92Met	missense_variant	3/5			ENSP00000501311.1
SOHLH1	ENST00000674066.1	n.2506C>A		non_coding_transcript_exon_variant	10/11

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 152202 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00385

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00411 AC: 1025 AN: 249290 Hom.: 7 AF XY: 0.00495 AC XY: 669 AN XY: 135150

Gnomad AFR exome AF: 0.000434

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00559

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0139

Gnomad FIN exome AF: 0.000142

Gnomad NFE exome AF: 0.00382

Gnomad OTH exome AF: 0.00459

GnomAD4 exome AF: 0.00405 AC: 5913 AN: 1460992 Hom.: 36 Cov.: 79 AF XY: 0.00449 AC XY: 3266 AN XY: 726778

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.00551

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0143

Gnomad4 FIN exome AF: 0.000152

Gnomad4 NFE exome AF: 0.00369

Gnomad4 OTH exome AF: 0.00431

GnomAD4 genome AF: 0.00280 AC: 426 AN: 152320 Hom.: 3 Cov.: 33 AF XY: 0.00291 AC XY: 217 AN XY: 74476

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00385

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00327 Hom.: 4

Bravo AF: 0.00265

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00399 AC: 484

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00510

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	SOHLH1: BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Mar 19, 2020

- -

SOHLH1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.38	T;T
MetaRNN	Benign	0.0080	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.65	N;N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.020	D;D
Polyphen		1.0	D;D
Vest4		0.30
MVP		0.77
MPC		0.24
ClinPred		0.048	T
GERP RS		3.2
Varity_R		0.15
gMVP		0.024

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

LitVar

Other links and lift over

dbSNP: rs144035874; hg19: chr9-138586263;