6-155256731-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_012454.4(TIAM2):c.4716T>A(p.Asp1572Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,614,194 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0022 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0026 (123 hom.)
• Consequence: TIAM2 NM_012454.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -7.35

Genes affected

TIAM2 (HGNC:11806): (TIAM Rac1 associated GEF 2) This gene encodes a guanine nucleotide exchange factor. A highly similar mouse protein specifically activates ras-related C3 botulinum substrate 1, converting this Rho-like guanosine triphosphatase (GTPase) from a guanosine diphosphate-bound inactive state to a guanosine triphosphate-bound active state. The encoded protein may play a role in neural cell development. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

TFB1M (HGNC:17037): (transcription factor B1, mitochondrial) The protein encoded by this gene is a dimethyltransferase that methylates the conserved stem loop of mitochondrial 12S rRNA. The encoded protein also is part of the basal mitochondrial transcription complex and is necessary for mitochondrial gene expression. The methylation and transcriptional activities of this protein are independent of one another. Variations in this gene may influence the severity of aminoglycoside-induced deafness (AID).[provided by RefSeq, Aug 2010]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001811415).
• BP6: Variant 6-155256731-T-A is Benign according to our data. Variant chr6-155256731-T-A is described in ClinVar as [Benign]. Clinvar id is 781889.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIAM2	NM_012454.4	c.4716T>A	p.Asp1572Glu	missense_variant	27/27	ENST00000682666.1
TFB1M	NM_016020.4	c.*1105A>T		3_prime_UTR_variant	7/7	ENST00000367166.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIAM2	ENST00000682666.1	c.4716T>A	p.Asp1572Glu	missense_variant	27/27		NM_012454.4	A2
TFB1M	ENST00000367166.5	c.*1105A>T		3_prime_UTR_variant	7/7	1	NM_016020.4	P1
	ENST00000435295.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 334 AN: 152186 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.0425

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00391 AC: 982 AN: 251470 Hom.: 16 AF XY: 0.00349 AC XY: 474 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00972

Gnomad EAS exome AF: 0.0383

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.000580

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00262 AC: 3825 AN: 1461890 Hom.: 123 Cov.: 37 AF XY: 0.00259 AC XY: 1884 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00907

Gnomad4 EAS exome AF: 0.0696

Gnomad4 SAS exome AF: 0.00219

Gnomad4 FIN exome AF: 0.00189

Gnomad4 NFE exome AF: 0.000318

Gnomad4 OTH exome AF: 0.00273

GnomAD4 genome AF: 0.00219 AC: 334 AN: 152304 Hom.: 6 Cov.: 31 AF XY: 0.00236 AC XY: 176 AN XY: 74470

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.0426

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00279 Hom.: 8

Bravo AF: 0.00206

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00418 AC: 507

Asia WGS AF: 0.0190 AC: 65 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.0040
Dann	Benign	0.95
DEOGEN2	Benign	0.026	T;.;.;.;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.79	T;T;T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.13	N;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N
REVEL	Benign	0.089
Sift	Benign	0.097	T;T;T;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T;T
Polyphen		0.023	B;B;B;.;B;.
Vest4		0.061
MutPred		0.25		Loss of helix (P = 0.0626);.;.;.;.;.;
MVP		0.085
MPC		0.21
ClinPred		0.037	T
GERP RS		-12
Varity_R		0.089
gMVP		0.12

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

LitVar

Other links and lift over

dbSNP: rs1571767; hg19: chr6-155577865;