NM_000883.4:c.561C>A

Variant names:

• chr7-128400835-G-T
• rs1042250
• NM_000883.4:c.561C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000883.4(IMPDH1):​c.561C>A​(p.Asn187Lys) variant causes a missense 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. 12/21 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N187N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IMPDH1 NM_000883.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.211
• Publications: 0 publications found

Genes affected

IMPDH1 (HGNC:6052): (inosine monophosphate dehydrogenase 1) The protein encoded by this gene acts as a homotetramer to regulate cell growth. The encoded protein is an enzyme that catalyzes the synthesis of xanthine monophosphate (XMP) from inosine-5'-monophosphate (IMP). This is the rate-limiting step in the de novo synthesis of guanine nucleotides. Defects in this gene are a cause of retinitis pigmentosa type 10 (RP10). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

IMPDH1 Gene-Disease associations (from GenCC):

• IMPDH1-related retinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Leber congenital amaurosis 11

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa 10

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28919148).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000883.4. 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
	IMPDH1	NM_000883.4	MANE Select	c.561C>A	p.Asn187Lys	missense	Exon 7 of 17	NP_000874.2
	IMPDH1	NM_001102605.2		c.531C>A	p.Asn177Lys	missense	Exon 6 of 16	NP_001096075.1	P20839-5
	IMPDH1	NM_001142576.2		c.462C>A	p.Asn154Lys	missense	Exon 6 of 16	NP_001136048.1	P20839-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IMPDH1	ENST00000338791.11	TSL:2 MANE Select	c.561C>A	p.Asn187Lys	missense	Exon 7 of 17	ENSP00000345096.6	P20839-6
	IMPDH1	ENST00000348127.11	TSL:1	c.453C>A	p.Asn151Lys	missense	Exon 5 of 15	ENSP00000265385.8	P20839-3
	IMPDH1	ENST00000955327.1		c.453C>A	p.Asn151Lys	missense	Exon 5 of 15	ENSP00000625386.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.72	N
PhyloP100		-0.21
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.30
Sift	Benign	0.35	T
Sift4G	Benign	0.49	T
Polyphen		0.040	B
Vest4		0.64
MutPred		0.42		Loss of helix (P = 0.0167)
MVP		0.65
MPC		0.69
ClinPred		0.81	D
GERP RS		-6.3
gMVP		0.79
Mutation Taster		=39/61	disease causing

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: rs1042250; hg19: chr7-128040889;