2-47005951-G-T

Variant names:

• chr2-47005951-G-T
• rs113844968
• NM_020458.4:c.1095G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020458.4(TTC7A):​c.1095G>T​(p.Val365Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00353 in 1,614,138 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (18 hom.)
• Consequence: TTC7A NM_020458.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.20
• Publications: 2 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]

TTC7A Gene-Disease associations (from GenCC):

• gastrointestinal defects and immunodeficiency syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• multiple intestinal atresia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-47005951-G-T is Benign according to our data. Variant chr2-47005951-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 458793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00283 (431/152260) while in subpopulation AMR AF = 0.0083 (127/15300). AF 95% confidence interval is 0.00713. There are 3 homozygotes in GnomAd4. There are 195 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.1095G>T	p.Val365Val	synonymous	Exon 9 of 20	NP_065191.2	Q9ULT0-1
	TTC7A	NM_001288951.2		c.1095G>T	p.Val365Val	synonymous	Exon 9 of 21	NP_001275880.1	Q9ULT0-4
	TTC7A	NM_001288953.2		c.993G>T	p.Val331Val	synonymous	Exon 10 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.1095G>T	p.Val365Val	synonymous	Exon 9 of 20	ENSP00000316699.5	Q9ULT0-1
	TTC7A	ENST00000394850.6	TSL:1	c.1095G>T	p.Val365Val	synonymous	Exon 9 of 21	ENSP00000378320.2	Q9ULT0-4
	TTC7A	ENST00000409825.5	TSL:1	n.*844G>T		non_coding_transcript_exon	Exon 10 of 21	ENSP00000386521.1	H0Y3V7

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152142 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00341

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00266 AC: 669 AN: 251440 AF XY: 0.00258

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00345

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00360 AC: 5259 AN: 1461878 Hom.: 18 Cov.: 31 AF XY: 0.00354 AC XY: 2576 AN XY: 727242

African (AFR) AF: 0.000896 AC: 30 AN: 33480

American (AMR) AF: 0.00496 AC: 222 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00451 AC: 118 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000765 AC: 66 AN: 86254

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53412

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00412 AC: 4585 AN: 1112008

Other (OTH) AF: 0.00368 AC: 222 AN: 60396

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152260 Hom.: 3 Cov.: 32 AF XY: 0.00262 AC XY: 195 AN XY: 74448

African (AFR) AF: 0.000770 AC: 32 AN: 41550

American (AMR) AF: 0.00830 AC: 127 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00341 AC: 232 AN: 68016

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00265 Hom.: 0

Bravo AF: 0.00355

EpiCase AF: 0.00316

EpiControl AF: 0.00362

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Multiple gastrointestinal atresias (1)
-	-	1	TTC7A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.39
DANN	Benign	0.70
PhyloP100		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs113844968; hg19: chr2-47233090;