rs140166160

chr2-47060786-C-Achr2-47060786-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020458.4(TTC7A):c.2170C>A(p.Gln724Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00688 in 1,609,952 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (52 hom.)
• Consequence: TTC7A NM_020458.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.22

Genes affected

TTC7A (HGNC:19750): (tetratricopeptide repeat domain 7A) This gene encodes a protein containing tetratricopeptide repeats. Mutations in this gene disrupt intestinal development and can cause early onset inflammatory bowel disease and intestinal atresia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

STPG4 (HGNC:26850): (sperm-tail PG-rich repeat containing 4) Predicted to enable chromatin binding activity and histone binding activity. Predicted to be involved in DNA demethylation of male pronucleus and positive regulation of DNA demethylation. Predicted to act upstream of or within C-5 methylation of cytosine. Predicted to be located in cytoplasm and nucleus. Predicted to be active in female pronucleus; germinal vesicle; and male pronucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004559338).
• BP6: Variant 2-47060786-C-A is Benign according to our data. Variant chr2-47060786-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 528469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47060786-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0045 (686/152336) while in subpopulation NFE AF= 0.00723 (492/68026). AF 95% confidence interval is 0.0067. There are 4 homozygotes in gnomad4. There are 341 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC7A	NM_020458.4	c.2170C>A	p.Gln724Lys	missense_variant	19/20	ENST00000319190.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC7A	ENST00000319190.11	c.2170C>A	p.Gln724Lys	missense_variant	19/20	2	NM_020458.4	P1

Frequencies

GnomAD3 genomes AF: 0.00451 AC: 686 AN: 152218 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00723

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00499 AC: 1246 AN: 249682 Hom.: 8 AF XY: 0.00549 AC XY: 740 AN XY: 134822

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00381

Gnomad ASJ exome AF: 0.00152

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00661

Gnomad FIN exome AF: 0.000836

Gnomad NFE exome AF: 0.00733

Gnomad OTH exome AF: 0.00459

GnomAD4 exome AF: 0.00713 AC: 10396 AN: 1457616 Hom.: 52 Cov.: 31 AF XY: 0.00706 AC XY: 5111 AN XY: 724414

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.00366

Gnomad4 ASJ exome AF: 0.00166

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00687

Gnomad4 FIN exome AF: 0.000919

Gnomad4 NFE exome AF: 0.00821

Gnomad4 OTH exome AF: 0.00653

GnomAD4 genome AF: 0.00450 AC: 686 AN: 152336 Hom.: 4 Cov.: 32 AF XY: 0.00458 AC XY: 341 AN XY: 74494

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00723

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00639 Hom.: 5

Bravo AF: 0.00457

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00482 AC: 585

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00709

EpiControl AF: 0.00706

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

TTC7A: BP4, BS2 -

Multiple gastrointestinal atresias Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	22
Dann	Benign	0.93
Eigen	Benign	0.039
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0046	T;T;T
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	0.92	N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.12	B;B;.
Vest4		0.26
MVP		0.81
MPC		0.078
ClinPred		0.0082	T
GERP RS		5.8
Varity_R		0.11
gMVP		0.40

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: rs140166160; hg19: chr2-47287925; COSMIC: COSV99766319; COSMIC: COSV99766319;