rs723077

Variant names:

• chr11-113323446-A-C
• rs723077
• NM_017868.4:c.217A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017868.4(TTC12):​c.217A>C​(p.Met73Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 1,573,520 control chromosomes in the GnomAD database, including 184,062 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13571 hom., cov: 32)
  • Exomes 𝑓: 0.49 (170491 hom.)
• Consequence: TTC12 NM_017868.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.10
• Publications: 49 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7309189E-4).
• BP6: Variant 11-113323446-A-C is Benign according to our data. Variant chr11-113323446-A-C is described in ClinVar as Benign. ClinVar VariationId is 1258984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017868.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC12	NM_017868.4	MANE Select	c.217A>C	p.Met73Leu	missense	Exon 3 of 22	NP_060338.3
	TTC12	NM_001318533.2		c.217A>C	p.Met73Leu	missense	Exon 3 of 22	NP_001305462.1
	TTC12	NM_001378063.1		c.142A>C	p.Met48Leu	missense	Exon 2 of 22	NP_001364992.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC12	ENST00000529221.6	TSL:2 MANE Select	c.217A>C	p.Met73Leu	missense	Exon 3 of 22	ENSP00000433757.1
	TTC12	ENST00000314756.7	TSL:1	c.217A>C	p.Met73Leu	missense	Exon 2 of 22	ENSP00000315160.3
	TTC12	ENST00000494714.5	TSL:1	n.217A>C		non_coding_transcript_exon	Exon 3 of 23	ENSP00000435291.1

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60535 AN: 151910 Hom.: 13575 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.442

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.420

GnomAD2 exomes AF: 0.468 AC: 104013 AN: 222224 AF XY: 0.475

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.518

Gnomad ASJ exome AF: 0.523

Gnomad EAS exome AF: 0.429

Gnomad FIN exome AF: 0.437

Gnomad NFE exome AF: 0.500

Gnomad OTH exome AF: 0.461

GnomAD4 exome AF: 0.486 AC: 690734 AN: 1421492 Hom.: 170491 Cov.: 32 AF XY: 0.486 AC XY: 343907 AN XY: 707032

African (AFR) AF: 0.158 AC: 4965 AN: 31400

American (AMR) AF: 0.496 AC: 17451 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 12569 AN: 24284

East Asian (EAS) AF: 0.395 AC: 15266 AN: 38682

South Asian (SAS) AF: 0.492 AC: 38541 AN: 78370

European-Finnish (FIN) AF: 0.445 AC: 23295 AN: 52358

Middle Eastern (MID) AF: 0.420 AC: 2355 AN: 5604

European-Non Finnish (NFE) AF: 0.500 AC: 549071 AN: 1097236

Other (OTH) AF: 0.466 AC: 27221 AN: 58366

GnomAD4 genome AF: 0.398 AC: 60531 AN: 152028 Hom.: 13571 Cov.: 32 AF XY: 0.398 AC XY: 29546 AN XY: 74308

African (AFR) AF: 0.180 AC: 7457 AN: 41474

American (AMR) AF: 0.442 AC: 6753 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 1814 AN: 3464

East Asian (EAS) AF: 0.416 AC: 2149 AN: 5164

South Asian (SAS) AF: 0.486 AC: 2336 AN: 4810

European-Finnish (FIN) AF: 0.445 AC: 4691 AN: 10552

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.498 AC: 33828 AN: 67964

Other (OTH) AF: 0.420 AC: 886 AN: 2110

Alfa AF: 0.468 Hom.: 80861

Bravo AF: 0.389

TwinsUK AF: 0.501 AC: 1859

ALSPAC AF: 0.495 AC: 1906

ESP6500AA AF: 0.194 AC: 852

ESP6500EA AF: 0.505 AC: 4339

ExAC AF: 0.461 AC: 56014

Asia WGS AF: 0.443 AC: 1538 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Ciliary dyskinesia, primary, 45 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.0010
DANN	Benign	0.38
DEOGEN2	Benign	0.0082	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.00017	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
PhyloP100		-1.1
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.011
Sift	Benign	0.96	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.017
MutPred		0.27		Loss of catalytic residue at M73 (P = 0.0084)
MPC		0.067
ClinPred		0.0067	T
GERP RS		-8.6
Varity_R		0.052
gMVP		0.12
Mutation Taster		=100/0	polymorphism (auto)

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: rs723077; hg19: chr11-113194168; COSMIC: COSV59097115; COSMIC: COSV59097115;