Genetic Variant NM_032303.5:c.395+8T>C (chr9-112409029-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032303.5(HSDL2):c.395+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,502,586 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 84 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 63 hom. )

Consequence

HSDL2
NM_032303.5 splice_region, intron

Scores

Splicing: ADA: 0.000008879

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.233

Publications

1 publications found

Variant links:

Genes affected

HSDL2 (HGNC:18572): (hydroxysteroid dehydrogenase like 2) Predicted to enable oxidoreductase activity. Located in mitochondrion and peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

HSDL2 links:

HSDL2-AS1 (HGNC:31438): (HSDL2 antisense RNA 1)

HSDL2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 9-112409029-T-C is Benign according to our data. Variant chr9-112409029-T-C is described in ClinVar as Benign. ClinVar VariationId is 781186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0549 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032303.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HSDL2	NM_032303.5	MANE Select	c.395+8T>C	splice_region intron	N/A	NP_115679.2
HSDL2	NM_001195822.2		c.280+3307T>C	intron	N/A	NP_001182751.1	Q6YN16-2
HSDL2	NR_036651.2		n.287+8T>C	splice_region intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HSDL2	ENST00000398805.8	TSL:1 MANE Select	c.395+8T>C	splice_region intron	N/A	ENSP00000381785.3	Q6YN16-1
HSDL2	ENST00000398803.1	TSL:1	c.280+3307T>C	intron	N/A	ENSP00000381783.1	Q6YN16-2
HSDL2	ENST00000942135.1		c.389+8T>C	splice_region intron	N/A	ENSP00000612194.1

Frequencies

GnomAD3 genomes

AF:

0.0163

AC:

2487

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0570

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00543

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.0144

GnomAD2 exomes

AF:

0.00410

AC:

974

AN:

237402

AF XY:

0.00293

show subpopulations

Gnomad AFR exome

AF:

0.0569

Gnomad AMR exome

AF:

0.00263

Gnomad ASJ exome

AF:

0.000106

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000818

Gnomad OTH exome

AF:

0.00139

GnomAD4 exome

AF:

0.00169

AC:

2279

AN:

1350300

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

947

AN XY:

677110

show subpopulations

African (AFR)

AF:

0.0605

AC:

1862

AN:

30782

American (AMR)

AF:

0.00336

AC:

139

AN:

41374

Ashkenazi Jewish (ASJ)

AF:

0.0000398

AC:

AN:

25118

East Asian (EAS)

AF:

0.00

AC:

AN:

39116

South Asian (SAS)

AF:

0.000208

AC:

AN:

81728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.00181

AC:

AN:

5534

European-Non Finnish (NFE)

AF:

0.0000443

AC:

AN:

1016652

Other (OTH)

AF:

0.00362

AC:

205

AN:

56660

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

104

209

313

418

522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0163

AC:

2488

AN:

152286

Hom.:

Cov.:

AF XY:

0.0160

AC XY:

1192

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0569

AC:

2362

AN:

41544

American (AMR)

AF:

0.00542

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68020

Other (OTH)

AF:

0.0142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

117

233

350

466

583

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00736

Hom.:

Bravo

AF:

0.0190

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.93

(source)

DANN

Benign

0.65

PhyloP100

0.23

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000089

dbscSNV1_RF

Benign

0.0

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over