Genetic Variant GDF11:p.Ala39del (chr12-55743400-CGCG-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BP6BS2

The NM_005811.5(GDF11):c.114_116delGGC(p.Ala39del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00696 in 965,392 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0080 ( 0 hom. )

Consequence

GDF11
NM_005811.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.25

Publications

0 publications found

Variant links:

Genes affected

GDF11 (HGNC:4216): (growth differentiation factor 11) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein plays a role in the development of the nervous and other organ systems, and may regulate aging. [provided by RefSeq, Aug 2016]

GDF11 Gene-Disease associations (from GenCC):

vertebral hypersegmentation and orofacial anomalies
Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

GDF11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_005811.5

BP6

Variant 12-55743400-CGCG-C is Benign according to our data. Variant chr12-55743400-CGCG-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3054165.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 163 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005811.5. 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
	GDF11	NM_005811.5	MANE Select	c.114_116delGGC	p.Ala39del	disruptive_inframe_deletion	Exon 1 of 3	NP_005802.1	O95390

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF11	ENST00000257868.10	TSL:1 MANE Select	c.114_116delGGC	p.Ala39del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000257868.5	O95390
	GDF11	ENST00000546799.1	TSL:1	c.30_32delGGC	p.Ala11del	disruptive_inframe_deletion	Exon 1 of 4	ENSP00000448390.1	H0YI30

Frequencies

GnomAD3 genomes

AF:

0.00111

AC:

162

AN:

145650

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00352

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000747

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.000240

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000610

Gnomad OTH

AF:

0.000497

GnomAD2 exomes

AF:

0.00230

AC:

AN:

434

AF XY:

0.00

show subpopulations

Gnomad FIN exome

AF:

0.00980

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00799

AC:

6552

AN:

819642

Hom.:

AF XY:

0.00820

AC XY:

3122

AN XY:

380906

show subpopulations

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

African (AFR)

AF:

0.0129

AC:

200

AN:

15462

American (AMR)

AF:

0.0214

AC:

AN:

1358

Ashkenazi Jewish (ASJ)

AF:

0.00938

AC:

AN:

5222

East Asian (EAS)

AF:

0.0125

AC:

AN:

3930

South Asian (SAS)

AF:

0.00785

AC:

132

AN:

16808

European-Finnish (FIN)

AF:

0.0344

AC:

AN:

1220

Middle Eastern (MID)

AF:

0.0110

AC:

AN:

1630

European-Non Finnish (NFE)

AF:

0.00778

AC:

5812

AN:

746934

Other (OTH)

AF:

0.00816

AC:

221

AN:

27078

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.253

Heterozygous variant carriers

981

1962

2943

3924

4905

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

292

584

876

1168

1460

<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

AF:

0.00112

AC:

163

AN:

145750

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

70864

show subpopulations

African (AFR)

AF:

0.00354

AC:

144

AN:

40694

American (AMR)

AF:

0.000746

AC:

AN:

14742

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3384

East Asian (EAS)

AF:

0.00

AC:

AN:

5018

South Asian (SAS)

AF:

0.000210

AC:

AN:

4770

European-Finnish (FIN)

AF:

0.000240

AC:

AN:

8316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000610

AC:

AN:

65594

Other (OTH)

AF:

0.000491

AC:

AN:

2036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

GDF11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.3

Mutation Taster

=74/26

polymorphism

(source)

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over