Variant rs104894904 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_015922.3(NSDHL):c.544G>A(p.Ala182Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000883 in 113,227 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. A182P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 1 hem., cov: 24)

Consequence

NSDHL
NM_015922.3 missense, splice_region

Scores

Splicing: ADA: 0.0008968

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.54

Variant links:

Genes affected

NSDHL (HGNC:13398): (NAD(P) dependent steroid dehydrogenase-like) The protein encoded by this gene is localized in the endoplasmic reticulum and is involved in cholesterol biosynthesis. Mutations in this gene are associated with CHILD syndrome, which is a X-linked dominant disorder of lipid metabolism with disturbed cholesterol biosynthesis, and typically lethal in males. Alternatively spliced transcript variants with differing 5' UTR have been found for this gene. [provided by RefSeq, Jul 2008]

NSDHL links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-152865819-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 11430.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.38112855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NSDHL	NM_015922.3 linkuse as main transcript	c.544G>A	p.Ala182Thr	missense_variant, splice_region_variant	6/8	ENST00000370274.8
NSDHL	NM_001129765.2 linkuse as main transcript	c.544G>A	p.Ala182Thr	missense_variant, splice_region_variant	7/9
NSDHL	XM_017029564.2 linkuse as main transcript	c.592G>A	p.Ala198Thr	missense_variant, splice_region_variant	6/8
NSDHL	XM_011531178.3 linkuse as main transcript	c.544G>A	p.Ala182Thr	missense_variant, splice_region_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
NSDHL	ENST00000370274.8 linkuse as main transcript	c.544G>A	p.Ala182Thr	missense_variant, splice_region_variant	6/8	1	NM_015922.3	P1
NSDHL	ENST00000440023.5 linkuse as main transcript	c.544G>A	p.Ala182Thr	missense_variant, splice_region_variant	7/9	5		P1
NSDHL	ENST00000432467.1 linkuse as main transcript	c.544G>A	p.Ala182Thr	missense_variant, splice_region_variant	7/8	3

Frequencies

GnomAD3 genomes

AF:

0.00000883

AC:

AN:

113227

Hom.:

Cov.:

AF XY:

0.0000283

AC XY:

AN XY:

35365

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000357

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000883

AC:

AN:

113227

Hom.:

Cov.:

AF XY:

0.0000283

AC XY:

AN XY:

35365

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000357

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.0073

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Uncertain

0.64

D;D;D

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.82

T;.;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.38

T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.73

N;N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.65

N;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.30

T;T;T

Sift4G

Benign

0.35

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.10

MutPred

0.63

Loss of stability (P = 0.0885);Loss of stability (P = 0.0885);Loss of stability (P = 0.0885);

MVP

0.94

MPC

0.21

ClinPred

0.067

GERP RS

3.0

Varity_R

0.14

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00090

dbscSNV1_RF

Benign

0.13

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over