11-30233736-G-C

Variant summary

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

The NM_001382289.1(FSHB):c.326G>C(p.Ser109Thr) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S109R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FSHB NM_001382289.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0960

Genes affected

FSHB (HGNC:3964): (follicle stimulating hormone subunit beta) The pituitary glycoprotein hormone family includes follicle-stimulating hormone, luteinizing hormone, chorionic gonadotropin, and thyroid-stimulating hormone. All of these glycoproteins consist of an identical alpha subunit and a hormone-specific beta subunit. This gene encodes the beta subunit of follicle-stimulating hormone. In conjunction with luteinizing hormone, follicle-stimulating hormone induces egg and sperm production. Alternative splicing results in two transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

ARL14EP-DT (HGNC:55517): (ARL14EP divergent transcript)

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=0.09214291).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FSHB	NM_001382289.1	c.326G>C	p.Ser109Thr	missense_variant	3/3	ENST00000533718.2
ARL14EP-DT	XR_007062639.1	n.351+83154C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FSHB	ENST00000533718.2	c.326G>C	p.Ser109Thr	missense_variant	3/3	1	NM_001382289.1	P1
ARL14EP-DT	ENST00000662729.1	n.293-76883C>G		intron_variant, non_coding_transcript_variant
FSHB	ENST00000254122.8	c.326G>C	p.Ser109Thr	missense_variant	3/3	5		P1
FSHB	ENST00000417547.1	c.326G>C	p.Ser109Thr	missense_variant	3/3	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

The c.326G>C (p.S109T) alteration is located in exon 3 (coding exon 2) of the FSHB gene. This alteration results from a G to C substitution at nucleotide position 326, causing the serine (S) at amino acid position 109 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	14
Dann	Benign	0.43
DEOGEN2	Uncertain	0.56	D;D;D
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.70	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.092	T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.19	N;N;N
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.39	N;N;N
REVEL	Benign	0.24
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.10
MutPred		0.48		Loss of disorder (P = 0.0861);Loss of disorder (P = 0.0861);Loss of disorder (P = 0.0861);
MVP		0.86
MPC		0.19
ClinPred		0.12	T
GERP RS		3.1
Varity_R		0.24
gMVP		0.69

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

LitVar

Other links and lift over

dbSNP: rs968644385; hg19: chr11-30255283;