chr9-135694417-G-T

Variant names:

• chr9-135694417-G-T
• rs144035874
• NM_001101677.2:c.916C>A

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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
• Publications: 6 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 772940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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.916C>A	p.Leu306Met	missense	Exon 7 of 8	NP_001095147.2	Q5JUK2-2
	SOHLH1	NM_001012415.3		c.916C>A	p.Leu306Met	missense	Exon 7 of 7	NP_001012415.3	Q5JUK2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOHLH1	ENST00000425225.2	TSL:5 MANE Select	c.916C>A	p.Leu306Met	missense	Exon 7 of 8	ENSP00000404438.1	Q5JUK2-2
	SOHLH1	ENST00000298466.9	TSL:1	c.916C>A	p.Leu306Met	missense	Exon 7 of 7	ENSP00000298466.5	Q5JUK2-1
	SOHLH1	ENST00000950496.1		c.916C>A	p.Leu306Met	missense	Exon 9 of 10	ENSP00000620555.1

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

GnomAD2 exomes AF: 0.00411 AC: 1025 AN: 249290 AF XY: 0.00495

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 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

African (AFR) AF: 0.000299 AC: 10 AN: 33478

American (AMR) AF: 0.00255 AC: 114 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00551 AC: 144 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0143 AC: 1230 AN: 86254

European-Finnish (FIN) AF: 0.000152 AC: 8 AN: 52576

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5768

European-Non Finnish (NFE) AF: 0.00369 AC: 4101 AN: 1111988

Other (OTH) AF: 0.00431 AC: 260 AN: 60378

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

African (AFR) AF: 0.000746 AC: 31 AN: 41568

American (AMR) AF: 0.00261 AC: 40 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4818

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00385 AC: 262 AN: 68034

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00321 Hom.: 6

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	SOHLH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs144035874; hg19: chr9-138586263;