rs768525725

Variant names:

• chr1-115033447-A-C
• NM_000549.5:c.85A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-115033447-A-C
• chr1-115033447-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000549.5(TSHB):​c.85A>C​(p.Met29Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. M29V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSHB NM_000549.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.99

Genes affected

TSHB (HGNC:12372): (thyroid stimulating hormone subunit beta) The four human glycoprotein hormones chorionic gonadotropin (CG), luteinizing hormone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH) are dimers consisting of alpha and beta subunits that are associated noncovalently. The alpha subunits of these hormones are identical, however, their beta chains are unique and confer biological specificity. Thyroid stimulating hormone functions in the control of thyroid structure and metabolism. The protein encoded by this gene is the beta subunit of thyroid stimulating hormone. Mutations in this gene are associated with congenital central and secondary hypothyroidism and Hashimoto's thyroiditis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20309925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHB	NM_000549.5	c.85A>C	p.Met29Leu	missense_variant	Exon 2 of 3	ENST00000256592.3	NP_000540.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHB	ENST00000256592.3	c.85A>C	p.Met29Leu	missense_variant	Exon 2 of 3	5	NM_000549.5	ENSP00000256592.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461164 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726920

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Benign	0.73
DEOGEN2	Uncertain	0.45	T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	T;.
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.86	L;L
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.12	N;N
REVEL	Benign	0.26
Sift	Benign	0.50	T;T
Sift4G	Benign	0.94	T;T
Polyphen		0.0080	B;B
Vest4		0.23
MutPred		0.48		Gain of catalytic residue at M29 (P = 0.0352);Gain of catalytic residue at M29 (P = 0.0352);
MVP		0.54
MPC		0.29
ClinPred		0.69	D
GERP RS		5.0
Varity_R		0.23
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr1-115576068;