chr11-113323371-A-G

Variant names:

• chr11-113323371-A-G
• rs148853643
• NM_017868.4:c.142A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_017868.4(TTC12):​c.142A>G​(p.Met48Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000477 in 1,613,584 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (3 hom.)
• Consequence: TTC12 NM_017868.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0390
• Publications: 2 publications found

Genes affected

TTC12 (HGNC:23700): (tetratricopeptide repeat domain 12) Involved in axonemal dynein complex assembly and sperm axoneme assembly. Located in centrosome and cytoplasm. Implicated in primary ciliary dyskinesia 45. [provided by Alliance of Genome Resources, Apr 2022]

TTC12 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 45

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052766204).
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC12	NM_017868.4	c.142A>G	p.Met48Val	missense_variant	Exon 3 of 22	ENST00000529221.6	NP_060338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC12	ENST00000529221.6	c.142A>G	p.Met48Val	missense_variant	Exon 3 of 22	2	NM_017868.4	ENSP00000433757.1

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 411 AN: 152176 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00953

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.000626 AC: 157 AN: 250824 AF XY: 0.000420

Gnomad AFR exome AF: 0.00868

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000245 AC: 358 AN: 1461290 Hom.: 3 Cov.: 30 AF XY: 0.000180 AC XY: 131 AN XY: 726970

African (AFR) AF: 0.00872 AC: 292 AN: 33468

American (AMR) AF: 0.000471 AC: 21 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111784

Other (OTH) AF: 0.000547 AC: 33 AN: 60366

GnomAD4 genome AF: 0.00271 AC: 412 AN: 152294 Hom.: 4 Cov.: 32 AF XY: 0.00269 AC XY: 200 AN XY: 74474

African (AFR) AF: 0.00953 AC: 396 AN: 41572

American (AMR) AF: 0.000523 AC: 8 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00118 Hom.: 3

Bravo AF: 0.00313

ESP6500AA AF: 0.00954 AC: 42

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000807 AC: 98

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.142A>G (p.M48V) alteration is located in exon 3 (coding exon 2) of the TTC12 gene. This alteration results from a A to G substitution at nucleotide position 142, causing the methionine (M) at amino acid position 48 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	3.9
DANN	Benign	0.81
DEOGEN2	Benign	0.012	T;T;T;.;.;.;T;.;.;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.56	T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.0053	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M;.;.;.;.;.;.;.;M;.
PhyloP100		-0.039
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.40	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.055
Sift	Benign	0.42	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.31	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0060	B;.;.;.;.;.;.;.;.;.
Vest4		0.045
MVP		0.15
MPC		0.074
ClinPred		0.0056	T
GERP RS		-2.5
Varity_R		0.066
gMVP		0.18
Mutation Taster		=100/0	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: rs148853643; hg19: chr11-113194093;