2-48962622-A-G

Variant names:

• chr2-48962622-A-G
• rs140106399
• NM_000145.4:c.*111T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000145.4(FSHR):​c.*111T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000925 in 1,108,632 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (7 hom.)
• Consequence: FSHR NM_000145.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.357
• Publications: 1 publications found

Genes affected

FSHR (HGNC:3969): (follicle stimulating hormone receptor) The protein encoded by this gene belongs to family 1 of G-protein coupled receptors. It is the receptor for follicle stimulating hormone and functions in gonad development. Mutations in this gene cause ovarian dysgenesis type 1, and also ovarian hyperstimulation syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

FSHR Gene-Disease associations (from GenCC):

• ovarian hyperstimulation syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ovarian dysgenesis 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 46 XX gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MIR548BAHG (HGNC:58158):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-48962622-A-G is Benign according to our data. Variant chr2-48962622-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 336478.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00104 (159/152368) while in subpopulation EAS AF = 0.0293 (152/5188). AF 95% confidence interval is 0.0255. There are 2 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000145.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FSHR	NM_000145.4	MANE Select	c.*111T>C		3_prime_UTR	Exon 10 of 10	NP_000136.2
	FSHR	NM_181446.3		c.*111T>C		3_prime_UTR	Exon 9 of 9	NP_852111.2	P23945-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FSHR	ENST00000406846.7	TSL:1 MANE Select	c.*111T>C		3_prime_UTR	Exon 10 of 10	ENSP00000384708.2	P23945-1
	MIR548BAHG	ENST00000634588.1	TSL:5	n.492+16217A>G		intron	N/A
	FSHR	ENST00000304421.8	TSL:1	c.*111T>C		downstream_gene	N/A	ENSP00000306780.4	P23945-3

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 162 AN: 152250 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0294

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.000906 AC: 866 AN: 956264 Hom.: 7 Cov.: 13 AF XY: 0.000806 AC XY: 397 AN XY: 492602

African (AFR) AF: 0.00 AC: 0 AN: 23426

American (AMR) AF: 0.0000510 AC: 2 AN: 39226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22220

East Asian (EAS) AF: 0.0221 AC: 788 AN: 35700

South Asian (SAS) AF: 0.000496 AC: 35 AN: 70596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3514

European-Non Finnish (NFE) AF: 0.00000741 AC: 5 AN: 674328

Other (OTH) AF: 0.000826 AC: 36 AN: 43600

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152368 Hom.: 2 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74516

African (AFR) AF: 0.00 AC: 0 AN: 41592

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0293 AC: 152 AN: 5188

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000559 Hom.: 0

Bravo AF: 0.00138

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Ovarian dysgenesis 1 (1)
-	-	1	Ovarian hyperstimulation syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.1
DANN	Benign	0.82
PhyloP100		0.36
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs140106399; hg19: chr2-49189761;