rs11564716

Variant names:

• chr11-2167446-C-G
• NM_000360.4:c.684G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-2167446-C-G
• chr11-2167446-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000360.4(TH):​c.684G>C​(p.Glu228Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,410,868 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. Synonymous variant affecting the same amino acid position (i.e. E228E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.856

Genes affected

TH (HGNC:11782): (tyrosine hydroxylase) The protein encoded by this gene is involved in the conversion of tyrosine to dopamine. It is the rate-limiting enzyme in the synthesis of catecholamines, hence plays a key role in the physiology of adrenergic neurons. Mutations in this gene have been associated with autosomal recessive Segawa syndrome. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4	c.684G>C	p.Glu228Asp	missense_variant	Exon 6 of 13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.777G>C	p.Glu259Asp	missense_variant	Exon 7 of 14		NP_954986.2
TH	NM_199293.3	c.765G>C	p.Glu255Asp	missense_variant	Exon 7 of 14		NP_954987.2
TH	XM_011520335.3	c.696G>C	p.Glu232Asp	missense_variant	Exon 6 of 13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.684G>C	p.Glu228Asp	missense_variant	Exon 6 of 13	1	NM_000360.4	ENSP00000325951.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410868 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 696992

Gnomad4 AFR exome AF: 0.00

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: 9.21e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L;.;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.7	D;D;.;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0090	D;D;.;D
Sift4G	Uncertain	0.020	D;D;D;D
Polyphen		0.14	B;B;.;P
Vest4		0.80
MutPred		0.86		Loss of ubiquitination at K264 (P = 0.063);.;.;.;
MVP		0.98
MPC		0.28
ClinPred		0.97	D
GERP RS		0.23
Varity_R		0.77
gMVP		0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-2188676;