Genetic Variant FSHB:p.Lys2Asn (chr11-30231908-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001382289.1(FSHB):c.6G>T(p.Lys2Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,510 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. K2K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FSHB
NM_001382289.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.19

Publications

0 publications found

Variant links:

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]

FSHB links:

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

ARL14EP-DT links:

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ACMG classification

Classification was made for transcript

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, 0.746

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382289.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FSHB	NM_001382289.1	MANE Select	c.6G>T	p.Lys2Asn	missense	Exon 2 of 3	NP_001369218.1	A0A0F7RQE8
FSHB	NM_000510.4		c.6G>T	p.Lys2Asn	missense	Exon 2 of 3	NP_000501.1	P01225
FSHB	NM_001018080.3		c.6G>T	p.Lys2Asn	missense	Exon 2 of 3	NP_001018090.1	A0A0F7RQE8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FSHB	ENST00000533718.2	TSL:1 MANE Select	c.6G>T	p.Lys2Asn	missense	Exon 2 of 3	ENSP00000433424.1	P01225
FSHB	ENST00000254122.8	TSL:5	c.6G>T	p.Lys2Asn	missense	Exon 2 of 3	ENSP00000254122.3	P01225
FSHB	ENST00000417547.1	TSL:5	c.6G>T	p.Lys2Asn	missense	Exon 2 of 3	ENSP00000416606.1	P01225

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461510

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727054

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111776

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.28

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.75

MetaSVM

Uncertain

-0.23

MutationAssessor

Uncertain

2.6

PhyloP100

3.2

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.97

REVEL

Benign

0.15

Sift

Uncertain

0.015

Sift4G

Benign

0.10

Polyphen

0.92

Vest4

0.50

MutPred

0.33

Loss of ubiquitination at K2 (P = 0.0174)

MVP

0.89

MPC

0.62

ClinPred

0.84

GERP RS

3.9

Varity_R

0.12

gMVP

0.69

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over