6-155257108-A-T

Variant names:

• chr6-155257108-A-T
• rs199608026
• NM_012454.4:c.5093A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_012454.4(TIAM2):​c.5093A>T​(p.His1698Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,394 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: TIAM2 NM_012454.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018265992).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012454.4. 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
	TIAM2	NM_012454.4	MANE Select	c.5093A>T	p.His1698Leu	missense	Exon 27 of 27	NP_036586.3
	TFB1M	NM_016020.4	MANE Select	c.*728T>A		3_prime_UTR	Exon 7 of 7	NP_057104.2	E5KTM5
	TIAM2	NM_001384546.1		c.5093A>T	p.His1698Leu	missense	Exon 27 of 27	NP_001371475.1	Q8IVF5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIAM2	ENST00000682666.1	MANE Select	c.5093A>T	p.His1698Leu	missense	Exon 27 of 27	ENSP00000507157.1	Q8IVF5-1
	TIAM2	ENST00000456877.6	TSL:1	c.3029A>T	p.His1010Leu	missense	Exon 21 of 21	ENSP00000407183.2	Q8IVF5-4
	TIAM2	ENST00000275246.11	TSL:1	c.1868A>T	p.His623Leu	missense	Exon 13 of 13	ENSP00000275246.7	Q8IVF5-3

Frequencies

GnomAD3 genomes AF: 0.0000462 AC: 7 AN: 151568 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00137

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000111 AC: 28 AN: 251324 AF XY: 0.000132

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00147

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461708 Hom.: 0 Cov.: 37 AF XY: 0.0000234 AC XY: 17 AN XY: 727152

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

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000655 AC: 26 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111894

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151686 Hom.: 0 Cov.: 31 AF XY: 0.0000540 AC XY: 4 AN XY: 74094

African (AFR) AF: 0.00 AC: 0 AN: 41332

American (AMR) AF: 0.00 AC: 0 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00137 AC: 7 AN: 5096

South Asian (SAS) AF: 0.00 AC: 0 AN: 4780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67946

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000824 AC: 10

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.019	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.040	D
Polyphen		0.99	D
Vest4		0.32
MVP		0.30
MPC		0.77
ClinPred		0.12	T
GERP RS		4.7
Varity_R		0.15
gMVP		0.11
Mutation Taster		=92/8	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: rs199608026; hg19: chr6-155578242;