12-56923954-C-A

Variant names:

• chr12-56923954-C-A
• rs199883998
• NM_148897.3:c.821G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_148897.3(SDR9C7):​c.821G>T​(p.Arg274Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R274C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SDR9C7 NM_148897.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.96
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• ichthyosis, congenital, autosomal recessive 13

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• lamellar ichthyosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_148897.3. 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
	SDR9C7	NM_148897.3	MANE Select	c.821G>T	p.Arg274Leu	missense	Exon 4 of 4	NP_683695.1	Q8NEX9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDR9C7	ENST00000293502.2	TSL:1 MANE Select	c.821G>T	p.Arg274Leu	missense	Exon 4 of 4	ENSP00000293502.1	Q8NEX9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461806 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111940

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		4.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.51		Loss of disorder (P = 0.0437)
MVP		0.95
MPC		0.77
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.38
gMVP		0.58
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs199883998; hg19: chr12-57317738;