18-31595220-G-T

Variant names:

• chr18-31595220-G-T
• rs730881165
• NM_000371.4:c.301G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 7P and 2B. PM1 PM2 PM5 PP2 BP4_Moderate

The NM_000371.4(TTR):​c.301G>T​(p.Ala101Ser) 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 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A101V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.250
• Publications: 3 publications found

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

ENSG00000294516 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000371.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31595221-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 495842.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 108 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.0149 (below the threshold of 3.09). Trascript score misZ: 1.5458 (below the threshold of 3.09). GenCC associations: The gene is linked to familial amyloid neuropathy, amyloidosis, hereditary systemic 1, ATTRV122I amyloidosis, hereditary ATTR amyloidosis, heart conduction disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2579229).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000371.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTR	NM_000371.4	MANE Select	c.301G>T	p.Ala101Ser	missense	Exon 3 of 4	NP_000362.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTR	ENST00000237014.8	TSL:1 MANE Select	c.301G>T	p.Ala101Ser	missense	Exon 3 of 4	ENSP00000237014.4
	TTR	ENST00000649620.1		c.301G>T	p.Ala101Ser	missense	Exon 5 of 6	ENSP00000497927.1
	TTR	ENST00000610404.5	TSL:5	c.205G>T	p.Ala69Ser	missense	Exon 3 of 4	ENSP00000477599.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251436 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00 AC: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	0.011
DANN	Benign	0.54
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.25
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.14	N
REVEL	Uncertain	0.47
Sift	Benign	0.38	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.54		Gain of disorder (P = 0.0755)
MVP		0.87
MPC		0.43
ClinPred		0.064	T
GERP RS		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.79
Mutation Taster		=70/30	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: rs730881165; hg19: chr18-29175183;