Genetic Variant NM_000371.4:c.69+103A>G (chr18-31592074-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000371.4(TTR):c.69+103A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,121,304 control chromosomes in the GnomAD database, including 856 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.021 ( 108 hom., cov: 33)

Exomes 𝑓: 0.015 ( 748 hom. )

Consequence

TTR
NM_000371.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0250

Publications

1 publications found

Variant links:

Genes affected

TTR (HGNC:12405): (transthyretin) This gene encodes one of the three prealbumins, which include alpha-1-antitrypsin, transthyretin and orosomucoid. The encoded protein, transthyretin, is a homo-tetrameric carrier protein, which transports thyroid hormones in the plasma and cerebrospinal fluid. It is also involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein. The protein may also be involved in other intracellular processes including proteolysis, nerve regeneration, autophagy and glucose homeostasis. Mutations in this gene are associated with amyloid deposition, predominantly affecting peripheral nerves or the heart, while a small percentage of the gene mutations are non-amyloidogenic. The mutations are implicated in the etiology of several diseases, including amyloidotic polyneuropathy, euthyroid hyperthyroxinaemia, amyloidotic vitreous opacities, cardiomyopathy, oculoleptomeningeal amyloidosis, meningocerebrovascular amyloidosis and carpal tunnel syndrome. [provided by RefSeq, Aug 2017]

TTR Gene-Disease associations (from GenCC):

amyloidosis, hereditary systemic 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
familial amyloid neuropathy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hereditary ATTR amyloidosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
heart conduction disease
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
ATTRV122I amyloidosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TTR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4 link	c.69+103A>G		intron_variant	Intron 1 of 3	ENST00000237014.8	NP_000362.1	P02766E9KL36

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8 link	c.69+103A>G		intron_variant	Intron 1 of 3	1	NM_000371.4	ENSP00000237014.4		P02766

Frequencies

GnomAD3 genomes

AF:

0.0208

AC:

3164

AN:

152166

Hom.:

108

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0367

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0558

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0270

Gnomad SAS

AF:

0.117

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.0177

GnomAD4 exome

AF:

0.0150

AC:

14500

AN:

969020

Hom.:

748

AF XY:

0.0179

AC XY:

8996

AN XY:

502868

show subpopulations

African (AFR)

AF:

0.0358

AC:

857

AN:

23926

American (AMR)

AF:

0.0733

AC:

3145

AN:

42928

Ashkenazi Jewish (ASJ)

AF:

0.000744

AC:

AN:

22864

East Asian (EAS)

AF:

0.0298

AC:

1109

AN:

37256

South Asian (SAS)

AF:

0.110

AC:

8303

AN:

75498

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50058

Middle Eastern (MID)

AF:

0.00710

AC:

AN:

4788

European-Non Finnish (NFE)

AF:

0.000481

AC:

321

AN:

667560

Other (OTH)

AF:

0.0162

AC:

714

AN:

44142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

692

1384

2076

2768

3460

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

174

348

522

696

870

<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:

0.0209

AC:

3180

AN:

152284

Hom.:

108

Cov.:

AF XY:

0.0226

AC XY:

1682

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0369

AC:

1532

AN:

41554

American (AMR)

AF:

0.0559

AC:

855

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.0268

AC:

139

AN:

5182

South Asian (SAS)

AF:

0.117

AC:

565

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000676

AC:

AN:

68016

Other (OTH)

AF:

0.0189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

151

301

452

602

753

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0123

Hom.:

Bravo

AF:

0.0243

Asia WGS

AF:

0.109

AC:

382

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

9.1

(source)

DANN

Benign

0.83

PhyloP100

-0.025

PromoterAI

0.025

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over