17-74748804-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004252.5(NHERF1):c.-43C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,531,540 control chromosomes in the GnomAD database, including 190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0079 (10 hom., cov: 33)
  • Exomes 𝑓: 0.014 (180 hom.)
• Consequence: NHERF1 NM_004252.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.204

Genes affected

NHERF1 (HGNC:11075): (NHERF family PDZ scaffold protein 1) This gene encodes a sodium/hydrogen exchanger regulatory cofactor. The protein interacts with and regulates various proteins including the cystic fibrosis transmembrane conductance regulator and G-protein coupled receptors such as the beta2-adrenergic receptor and the parathyroid hormone 1 receptor. The protein also interacts with proteins that function as linkers between integral membrane and cytoskeletal proteins. The protein localizes to actin-rich structures including membrane ruffles, microvilli, and filopodia. Mutations in this gene result in hypophosphatemic nephrolithiasis/osteoporosis type 2, and loss of heterozygosity of this gene is implicated in breast cancer.[provided by RefSeq, Sep 2009]

SLC9A3R1-AS1 (HGNC:55322): (SLC9A3R1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 17-74748804-C-A is Benign according to our data. Variant chr17-74748804-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1316123.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00787 (1198/152272) while in subpopulation SAS AF= 0.0188 (91/4830). AF 95% confidence interval is 0.0157. There are 10 homozygotes in gnomad4. There are 542 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1197 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHERF1	NM_004252.5	c.-43C>A		5_prime_UTR_variant	1/6	ENST00000262613.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHERF1	ENST00000262613.10	c.-43C>A		5_prime_UTR_variant	1/6	1	NM_004252.5	P1
SLC9A3R1-AS1	ENST00000585285.1	n.109G>T		non_coding_transcript_exon_variant	1/2	3
NHERF1	ENST00000583369.5	c.-43C>A		5_prime_UTR_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.00787 AC: 1197 AN: 152154 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.0104 AC: 1712 AN: 164426 Hom.: 22 AF XY: 0.0115 AC XY: 1046 AN XY: 91072

Gnomad AFR exome AF: 0.00290

Gnomad AMR exome AF: 0.00574

Gnomad ASJ exome AF: 0.00524

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0197

Gnomad FIN exome AF: 0.00247

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.00881

GnomAD4 exome AF: 0.0144 AC: 19909 AN: 1379268 Hom.: 180 Cov.: 27 AF XY: 0.0147 AC XY: 10070 AN XY: 684374

Gnomad4 AFR exome AF: 0.00223

Gnomad4 AMR exome AF: 0.00591

Gnomad4 ASJ exome AF: 0.00629

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0200

Gnomad4 FIN exome AF: 0.00307

Gnomad4 NFE exome AF: 0.0160

Gnomad4 OTH exome AF: 0.0105

GnomAD4 genome AF: 0.00787 AC: 1198 AN: 152272 Hom.: 10 Cov.: 33 AF XY: 0.00728 AC XY: 542 AN XY: 74456

Gnomad4 AFR AF: 0.00255

Gnomad4 AMR AF: 0.00483

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0188

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.0128

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00864 Hom.: 2

Bravo AF: 0.00779

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	7.2
Dann	Benign	0.84

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: rs147405067; hg19: chr17-72744943;