NM_014425.5:c.-155C>T

Variant names:

• chr9-100099286-C-T
• rs62577237
• NM_014425.5:c.-155C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014425.5(INVS):​c.-155C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00899 in 160,600 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0087 (19 hom., cov: 32)
  • Exomes 𝑓: 0.014 (1 hom.)
• Consequence: INVS NM_014425.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.928
• Publications: 3 publications found

Genes affected

INVS (HGNC:17870): (inversin) This gene encodes a protein containing multiple ankyrin domains and two IQ calmodulin-binding domains. The encoded protein may function in renal tubular development and function, and in left-right axis determination. This protein interacts with nephrocystin and infers a connection between primary cilia function and left-right axis determination. A similar protein in mice interacts with calmodulin. Mutations in this gene have been associated with nephronophthisis type 2. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, May 2012]

ERP44 (HGNC:18311): (endoplasmic reticulum protein 44) This gene encodes a member of the protein disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins. It has an inferred N-terminal signal peptide, a catalytically active thioredoxin (TRX) domain, two TRX-like domains and a C-terminal ER-retention sequence. This protein functions as a pH-regulated chaperone of the secretory pathway and likely plays a role in protein quality control at the endoplasmic reticulum - Golgi interface. [provided by RefSeq, Dec 2016]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 9-100099286-C-T is Benign according to our data. Variant chr9-100099286-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 364218.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00871 (1327/152302) while in subpopulation SAS AF = 0.0267 (129/4826). AF 95% confidence interval is 0.023. There are 19 homozygotes in GnomAd4. There are 673 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014425.5. 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
	INVS	NM_014425.5	MANE Select	c.-155C>T		5_prime_UTR	Exon 1 of 17	NP_055240.2
	INVS	NM_001318381.2		c.-531C>T		5_prime_UTR	Exon 1 of 18	NP_001305310.1
	INVS	NM_001318382.2		c.-1144C>T		5_prime_UTR	Exon 1 of 17	NP_001305311.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INVS	ENST00000262457.7	TSL:1 MANE Select	c.-155C>T		5_prime_UTR	Exon 1 of 17	ENSP00000262457.2	Q9Y283-1
	INVS	ENST00000885859.1		c.-266C>T		5_prime_UTR	Exon 1 of 18	ENSP00000555918.1
	INVS	ENST00000885858.1		c.-155C>T		5_prime_UTR	Exon 1 of 16	ENSP00000555917.1

Frequencies

GnomAD3 genomes AF: 0.00873 AC: 1329 AN: 152184 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.00376

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.0141 AC: 117 AN: 8298 Hom.: 1 Cov.: 0 AF XY: 0.0181 AC XY: 87 AN XY: 4812

African (AFR) AF: 0.00 AC: 0 AN: 96

American (AMR) AF: 0.00 AC: 0 AN: 174

Ashkenazi Jewish (ASJ) AF: 0.0250 AC: 3 AN: 120

East Asian (EAS) AF: 0.00 AC: 0 AN: 90

South Asian (SAS) AF: 0.0273 AC: 68 AN: 2488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 22

European-Non Finnish (NFE) AF: 0.00933 AC: 43 AN: 4608

Other (OTH) AF: 0.00820 AC: 3 AN: 366

GnomAD4 genome AF: 0.00871 AC: 1327 AN: 152302 Hom.: 19 Cov.: 32 AF XY: 0.00904 AC XY: 673 AN XY: 74464

African (AFR) AF: 0.00195 AC: 81 AN: 41584

American (AMR) AF: 0.00464 AC: 71 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.0267 AC: 129 AN: 4826

European-Finnish (FIN) AF: 0.00376 AC: 40 AN: 10626

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0129 AC: 876 AN: 68024

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0116 Hom.: 23

Bravo AF: 0.00812

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Infantile nephronophthisis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.2
DANN	Benign	0.85
PhyloP100		-0.93
PromoterAI		0.041	Neutral
Mutation Taster		=300/0	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: rs62577237; hg19: chr9-102861568;