12-56929515-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_148897.3(SDR9C7):c.599T>C(p.Ile200Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,612,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

SDR9C7
NM_148897.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 9.27

Variant links:

Genes affected

SDR9C7 (HGNC:29958): (short chain dehydrogenase/reductase family 9C member 7) This gene encodes a protein with similarity to the short-chain dehydrogenase/reductase (SDR) family but has not been shown to have retinoid or dehydrogenase activities. [provided by RefSeq, Apr 2010]

SDR9C7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.942

PP5

Variant 12-56929515-A-G is Pathogenic according to our data. Variant chr12-56929515-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDR9C7	NM_148897.3 link	c.599T>C	p.Ile200Thr	missense_variant	Exon 3 of 4	ENST00000293502.2	NP_683695.1	Q8NEX9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDR9C7	ENST00000293502.2 link	c.599T>C	p.Ile200Thr	missense_variant	Exon 3 of 4	1	NM_148897.3	ENSP00000293502.1		Q8NEX9

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152146

Hom.:

Cov.:

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251232

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000507

AC:

AN:

1460220

Hom.:

Cov.:

AF XY:

0.0000551

AC XY:

AN XY:

726042

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000621

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ichthyosis, congenital, autosomal recessive 13

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 14, 2017	- -

SDR9C7-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 02, 2022

The SDR9C7 c.599T>C variant is predicted to result in the amino acid substitution p.Ile200Thr. This variant was reported in the homozygous multiple related individuals with ichthyosis and was found to segregate with disease (Shigehara et al. 2016. PubMed ID: 28173123). In addition, the p.Ile200Thr change was found to be associated with reduced SDR9C7 protein expression in the cornified layer of the epidermis (Shigehara et al. 2016. PubMed ID: 28173123). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-57323299-A-G). This variant is interpreted as likely pathogenic. -

Lamellar ichthyosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 16, 2024

Variant summary: SDR9C7 c.599T>C (p.Ile200Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251232 control chromosomes. c.599T>C has been reported in the literature in multiple homozygous or compound heterozygous individuals affected with Lamellar Ichthyosis (Shigehara_2016, Seidl-Philipp_2019). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Shigehara_2016). The following publications have been ascertained in the context of this evaluation (PMID: 31012992, 28173123). ClinVar contains an entry for this variant (Variation ID: 430711). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 23, 2024

Segregates with disease in many affected individuals from multiple families in the published literature (PMID: 28173123, 31012992); Published functional studies demonstrate significantly reduced protein expression in vitro (PMID: 28173123); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27538420, 31012992, 28173123) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.82

M_CAP

Benign

0.038

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

-0.081

MutationAssessor

Pathogenic

3.7

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.97

Vest4

0.97

MutPred

0.80

Loss of catalytic residue at P202 (P = 0.0284);

MVP

0.82

MPC

0.56

ClinPred

0.99

GERP RS

5.2

Varity_R

0.80

gMVP

0.84

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over