Genetic Variant RETSAT:p.Pro559Ser (chr2-85343657-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017750.4(RETSAT):c.1675C>T(p.Pro559Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. P559T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 35)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RETSAT
NM_017750.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.67

Publications

2 publications found

Variant links:

Genes affected

RETSAT (HGNC:25991): (retinol saturase) Predicted to enable all-trans-retinol 13,14-reductase activity. Predicted to be involved in retinol metabolic process. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

RETSAT links:

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ACMG classification

Classification was made for transcript

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=0.2607325).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017750.4. 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
	RETSAT	NM_017750.4	MANE Select	c.1675C>T	p.Pro559Ser	missense	Exon 10 of 11	NP_060220.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RETSAT	ENST00000295802.9	TSL:1 MANE Select	c.1675C>T	p.Pro559Ser	missense	Exon 10 of 11	ENSP00000295802.4	Q6NUM9-1
RETSAT	ENST00000429806.5	TSL:1	n.*62C>T		non_coding_transcript_exon	Exon 7 of 8	ENSP00000388202.1	H7BZ81
RETSAT	ENST00000429806.5	TSL:1	n.*62C>T		3_prime_UTR	Exon 7 of 8	ENSP00000388202.1	H7BZ81

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150370

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000211

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

250800

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461352

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33350

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111752

Other (OTH)

AF:

0.0000166

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000133

AC:

AN:

150490

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73546

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000245

AC:

AN:

40886

American (AMR)

AF:

0.00

AC:

AN:

15058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3448

East Asian (EAS)

AF:

0.00

AC:

AN:

5050

South Asian (SAS)

AF:

0.000211

AC:

AN:

4740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10498

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67538

Other (OTH)

AF:

0.00

AC:

AN:

2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

ExAC

AF:

0.0000330

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.034

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.74

M_CAP

Benign

0.055

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.1

PhyloP100

2.7

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-4.8

REVEL

Benign

0.18

Sift

Benign

0.11

Sift4G

Benign

0.11

Polyphen

0.17

Vest4

0.21

MutPred

0.32

Loss of sheet (P = 0.1398)

MVP

0.51

MPC

0.098

ClinPred

0.12

GERP RS

4.1

Varity_R

0.14

gMVP

0.54

Mutation Taster

=93/7

polymorphism

(source)

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

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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