chr14-24296587-G-C

Variant names:

• chr14-24296587-G-C
• rs377106747
• NM_001136050.3:c.296C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001136050.3(DHRS1):​c.296C>G​(p.Thr99Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 18/26 in silico tools predict a benign outcome for this variant. 2/3 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. T99M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DHRS1 NM_001136050.3 missense, splice_region
• Scores: Splicing: ADA: 0.0001163
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53
• Publications: 0 publications found

Genes affected

DHRS1 (HGNC:16445): (dehydrogenase/reductase 1) This gene encodes a member of the short-chain dehydrogenases/reductases (SDR) family. The encoded enzyme contains a conserved catalytic domain and likely functions as an oxidoreductase. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Nov 2008]

NOP9 (HGNC:19826): (NOP9 nucleolar protein) Enables RNA binding activity. Predicted to be involved in ribosome biogenesis. Predicted to be part of 90S preribosome and preribosome, small subunit precursor. Predicted to be active in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000288044 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08619565).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136050.3. 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
	DHRS1	NM_001136050.3	MANE Select	c.296C>G	p.Thr99Arg	missense splice_region	Exon 4 of 9	NP_001129522.1	Q96LJ7
	DHRS1	NM_138452.3		c.296C>G	p.Thr99Arg	missense splice_region	Exon 4 of 9	NP_612461.1	Q96LJ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHRS1	ENST00000288111.12	TSL:1 MANE Select	c.296C>G	p.Thr99Arg	missense splice_region	Exon 4 of 9	ENSP00000288111.7	Q96LJ7
	DHRS1	ENST00000396813.5	TSL:2	c.296C>G	p.Thr99Arg	missense splice_region	Exon 4 of 9	ENSP00000380027.1	Q96LJ7
	DHRS1	ENST00000860257.1		c.296C>G	p.Thr99Arg	missense splice_region	Exon 5 of 10	ENSP00000530316.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.24	N
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.32	N
PhyloP100		1.5
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.21
Sift	Benign	0.10	T
Sift4G	Benign	0.24	T
Polyphen		0.051	B
Vest4		0.24
MutPred		0.53		Gain of MoRF binding (P = 0.0066)
MVP		0.49
MPC		0.26
ClinPred		0.057	T
GERP RS		0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.70
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs377106747; hg19: chr14-24765793;