2-47046329-A-G

Variant names:

• chr2-47046329-A-G
• rs139010200
• NM_020458.4:c.1817A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020458.4(TTC7A):​c.1817A>G​(p.Lys606Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00298 in 1,613,908 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (10 hom.)
• Consequence: TTC7A NM_020458.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 6.76
• Publications: 13 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015966624).
• BP6: Variant 2-47046329-A-G is Benign according to our data. Variant chr2-47046329-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242606.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00208 (317/152338) while in subpopulation NFE AF = 0.00343 (233/68026). AF 95% confidence interval is 0.00306. There are 1 homozygotes in GnomAd4. There are 141 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020458.4. 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
	TTC7A	NM_020458.4	MANE Select	c.1817A>G	p.Lys606Arg	missense	Exon 16 of 20	NP_065191.2	Q9ULT0-1
	TTC7A	NM_001288951.2		c.1817A>G	p.Lys606Arg	missense	Exon 16 of 21	NP_001275880.1	Q9ULT0-4
	TTC7A	NM_001288953.2		c.1715A>G	p.Lys572Arg	missense	Exon 17 of 21	NP_001275882.1	G5E9G4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC7A	ENST00000319190.11	TSL:2 MANE Select	c.1817A>G	p.Lys606Arg	missense	Exon 16 of 20	ENSP00000316699.5	Q9ULT0-1
	TTC7A	ENST00000394850.6	TSL:1	c.1817A>G	p.Lys606Arg	missense	Exon 16 of 21	ENSP00000378320.2	Q9ULT0-4
	TTC7A	ENST00000409825.5	TSL:1	n.*1566A>G		non_coding_transcript_exon	Exon 17 of 21	ENSP00000386521.1	H0Y3V7

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 317 AN: 152220 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00342

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00213 AC: 536 AN: 251304 AF XY: 0.00211

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00934

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00324

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00308 AC: 4499 AN: 1461570 Hom.: 10 Cov.: 31 AF XY: 0.00300 AC XY: 2180 AN XY: 727088

African (AFR) AF: 0.000538 AC: 18 AN: 33474

American (AMR) AF: 0.000604 AC: 27 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00953 AC: 249 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00114 AC: 61 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00350 AC: 3888 AN: 1111822

Other (OTH) AF: 0.00422 AC: 255 AN: 60380

GnomAD4 genome AF: 0.00208 AC: 317 AN: 152338 Hom.: 1 Cov.: 33 AF XY: 0.00189 AC XY: 141 AN XY: 74490

African (AFR) AF: 0.000313 AC: 13 AN: 41584

American (AMR) AF: 0.00111 AC: 17 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00343 AC: 233 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00318 Hom.: 2

Bravo AF: 0.00198

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00206 AC: 250

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00376

EpiControl AF: 0.00231

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	-	Gastrointestinal defects and immunodeficiency syndrome 1 (1)
-	-	1	Multiple gastrointestinal atresias (1)
-	1	-	not specified (1)
-	-	1	TTC7A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.74
MVP		0.74
MPC		0.36
ClinPred		0.63	D
GERP RS		5.5
Varity_R		0.64
gMVP		0.65
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs139010200; hg19: chr2-47273468; COSMIC: COSV99041414;