1-117074976-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003594.4(TTF2):c.392A>G(p.Lys131Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000344 in 1,614,030 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 30)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: TTF2 NM_003594.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.34

Genes affected

TTF2 (HGNC:12398): (transcription termination factor 2) This gene encodes a member of the SWI2/SNF2 family of proteins, which play a critical role in altering protein-DNA interactions. The encoded protein has been shown to have dsDNA-dependent ATPase activity and RNA polymerase II termination activity. This protein interacts with cell division cycle 5-like, associates with human splicing complexes, and plays a role in pre-mRNA splicing. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007492721).
• BP6: Variant 1-117074976-A-G is Benign according to our data. Variant chr1-117074976-A-G is described in ClinVar as [Benign]. Clinvar id is 741107.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTF2	NM_003594.4	c.392A>G	p.Lys131Arg	missense_variant	5/23	ENST00000369466.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTF2	ENST00000369466.9	c.392A>G	p.Lys131Arg	missense_variant	5/23	1	NM_003594.4	P1
TTF2	ENST00000470935.1	n.381A>G		non_coding_transcript_exon_variant	5/5	5

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 277 AN: 152028 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.00645

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000466 AC: 117 AN: 251304 Hom.: 0 AF XY: 0.000324 AC XY: 44 AN XY: 135830

Gnomad AFR exome AF: 0.00665

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000189 AC: 277 AN: 1461884 Hom.: 0 Cov.: 30 AF XY: 0.000160 AC XY: 116 AN XY: 727238

Gnomad4 AFR exome AF: 0.00741

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.00183 AC: 278 AN: 152146 Hom.: 2 Cov.: 30 AF XY: 0.00173 AC XY: 129 AN XY: 74390

Gnomad4 AFR AF: 0.00646

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000324 Hom.: 0

Bravo AF: 0.00215

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000659 AC: 80

Asia WGS AF: 0.00144 AC: 6 AN: 3478

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

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.041	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.0075	T
MetaSVM	Uncertain	0.55	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.38
Sift	Benign	0.099	T
Sift4G	Benign	0.13	T
Polyphen		0.95	P
Vest4		0.24
MVP		0.96
MPC		0.56
ClinPred		0.023	T
GERP RS		5.6
Varity_R		0.097
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs73006031; hg19: chr1-117617598;