chr18-31598647-C-T

Variant names:

• chr18-31598647-C-T
• rs28933981
• NM_000371.4:c.416C>T
• TTR p.Thr139Met

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-7 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -7 classification points (ACMG Germline Pathogenicity v2019). PP3BS2BP6_Strong

The NM_000371.4(TTR):c.416C>T (p.Thr139Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0027 (AC=4,364) in the gnomAD database across 1,614,166 control chromosomes, including 6 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0034. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.T139= (synonymous): Conflicting_classifications_of_pathogenicity (ClinVar VariationId 43455) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (6 hom.)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 B:12 O:1
• Conservation: PhyloP100: 6.09
• Publications: 60 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, STRONG Submitted by: G2P, PanelApp Australia
• familial amyloid neuropathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary ATTR amyloidosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• carpal tunnel syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• heart conduction disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• ATTRV122I amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000294516 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -7 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 0 star(s). ClinVar submissions strongly and reliably favor benignity (11/12 total B/LB).
	BS2Observed in healthy adult		Pure AD gene with cumulative gnomAD AC ≥5 — observed in healthy adults (BS2); GnomAD homozygous count = 6.; GnomAD homozygous count = 6 does not exceed known P/LP transcript maximum nhomalt = 8 — BS2 blocked.; Very high cumulative gnomAD AC = 4364 (any gene).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TTR NM_000371.4	MANE Select	c.416C>T p.Thr139Met	missense	Exon 4 of 4	Prot: NP_000362.1 UniProt:

TTR NM_000371.4

MANE Select

HGVSc / HGVSpc.416C>Tp.Thr139Met

Exon rankExon 4 of 4

missense

Prot: NP_000362.1UniProt: P02766

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TTR ENST00000237014.8	TSL:1MANE Select	c.416C>T p.Thr139Met	missense	Exon 4 of 4	Prot: ENSP00000237014.4 UniProt:
	TTR ENST00000649620.1		c.416C>T p.Thr139Met	missense	Exon 6 of 6	Prot: ENSP00000497927.1 UniProt:
	TTR ENST00000858988.1		c.416C>T p.Thr139Met	missense	Exon 6 of 6	Prot: ENSP00000529047.1 UniProt:

TTR ENST00000237014.8

TSL:1MANE Select

HGVSc / HGVSpc.416C>Tp.Thr139Met

Exon rankExon 4 of 4

missense

Prot: ENSP00000237014.4UniProt: P02766

TTR ENST00000649620.1

HGVSc / HGVSpc.416C>Tp.Thr139Met

Exon rankExon 6 of 6

missense

Prot: ENSP00000497927.1UniProt: P02766

TTR ENST00000858988.1

HGVSc / HGVSpc.416C>Tp.Thr139Met

Exon rankExon 6 of 6

missense

Prot: ENSP00000529047.1UniProt: P02766

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00172	AC:261	Hom:0	AN:152180	Cov:32
GnomAD2 exomes	AF: 0.00151	AC:379	Hom:	AN:251440	Cov:
GnomAD4 exome	AF: 0.00281	AC:4103	Hom:6	AN:1461868	Cov:31
GnomAD4 genome	AF: 0.00171	AC:261	Hom:0	AN:152298	Cov:32
TOPMed (Bravo)	AF: 0.00170	AC:449	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00228	AC:1102	Hom:4	AN:484088	Cov:
Local & regional cohorts 6 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00128	AC:3	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00223	AC:29	Hom:	AN:13006	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00	AC:0	Hom:0	AN:122732	Cov:
Turkish Variome	AF: 0.000298	AC:2	Hom:0	AN:6718	Cov:
UK10K	AF: 0.00450	AC:34	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000112	AC:1	Hom:0	AN:8960	Cov:

Showing 12 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00225 *	25	11108	0.00278 *	49	17618
BipEx(Bipolar disorder (including schizoaffective))	0.00419	119	28420	0.00288	83	28844
Epi25(Epilepsy)	0.00219	92	41958	0.00260	174	66886
SCHEMA(Schizophrenia)	0.00133	162	121726	0.00161	307	190572

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Amyloidosis, hereditary systemic 1 (3)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Charcot-Marie-Tooth disease (1)
1	-	-	Hyperthyroidism (1)
1	-	-	Hyperthyroxinemia, dystransthyretinemic (1)
-	-	-	AMYLOIDOSIS, HEREDITARY SYSTEMIC 1, MODIFIER OF (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
GPN-Star LLR	N/A	-6.5
GPN-Star score	N/A	6.5
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.050	T
MetaSVM	Pathogenic	0.90	D
Mutation Taster	N/A	34/66	disease causing
MutationAssessor	Pathogenic	3.3	M
PhyloP100	Uncertain	6.1
popEVE	Benign	-4.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.0	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0040	D
Varity_R	N/A	0.42
VESM-3B	Benign	-9.3

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs28933981;

hg19: chr18-29178610;

COSMIC: COSV52701482;

COSMIC: COSV52701482;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar