rs6357

Variant names:

• chr11-2167008-C-A
• rs6357
• NM_000360.4:c.720G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-2167008-C-A
• chr11-2167008-C-T

Variant summary

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

The NM_000360.4(TH):​c.720G>T​(p.Lys240Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,433,672 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. K240R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.75
• Publications: 0 publications found

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]

TH Gene-Disease associations (from GenCC):

• TH-deficient dopa-responsive dystonia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• tyrosine hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health

ENSG00000295384 (HGNC:):

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, 0.79

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4	c.720G>T	p.Lys240Asn	missense_variant	Exon 7 of 13	ENST00000352909.8	NP_000351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.720G>T	p.Lys240Asn	missense_variant	Exon 7 of 13	1	NM_000360.4	ENSP00000325951.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1433672 Hom.: 0 Cov.: 60 AF XY: 0.00 AC XY: 0 AN XY: 710628

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

African (AFR) AF: 0.00 AC: 0 AN: 32944

American (AMR) AF: 0.00 AC: 0 AN: 41204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25542

East Asian (EAS) AF: 0.00 AC: 0 AN: 38298

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098268

Other (OTH) AF: 0.00 AC: 0 AN: 59336

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.0042	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Pathogenic	0.84	D;.;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.7	L;.;.
PhyloP100		1.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.42	B;B;B
Vest4		0.49
MutPred		0.39		Loss of ubiquitination at K271 (P = 0.0255);.;.;
MVP		0.95
MPC		0.14
ClinPred		0.35	T
GERP RS		2.3
Varity_R		0.45
gMVP		0.66
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6357; hg19: chr11-2188238;