17-74748731-C-A

Variant names:

• chr17-74748731-C-A
• rs551803753
• NM_004252.5:c.-116C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004252.5(NHERF1):​c.-116C>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 0.00000129 in 774,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000013 (0 hom.)
• Consequence: NHERF1 NM_004252.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.875
• Publications: 0 publications found

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)

MIR3615 (HGNC:38905): (microRNA 3615) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004252.5. 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
	NHERF1	NM_004252.5	MANE Select	c.-116C>A		5_prime_UTR	Exon 1 of 6	NP_004243.1	O14745-1
	SLC9A3R1-AS1	NR_187307.1		n.1002G>T		non_coding_transcript_exon	Exon 2 of 3
	MIR3615	NR_037409.1		n.*32C>A		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHERF1	ENST00000262613.10	TSL:1 MANE Select	c.-116C>A		5_prime_UTR	Exon 1 of 6	ENSP00000262613.5	O14745-1
	NHERF1	ENST00000851804.1		c.-116C>A		5_prime_UTR	Exon 1 of 7	ENSP00000521863.1
	NHERF1	ENST00000851803.1		c.-116C>A		5_prime_UTR	Exon 1 of 6	ENSP00000521862.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000129 AC: 1 AN: 774392 Hom.: 0 Cov.: 10 AF XY: 0.00000255 AC XY: 1 AN XY: 392218

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 17220

American (AMR) AF: 0.00 AC: 0 AN: 20508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16298

East Asian (EAS) AF: 0.00 AC: 0 AN: 31210

South Asian (SAS) AF: 0.00 AC: 0 AN: 55042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4316

European-Non Finnish (NFE) AF: 0.00000178 AC: 1 AN: 562732

Other (OTH) AF: 0.00 AC: 0 AN: 36858

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	3.9
DANN	Benign	0.77
PhyloP100		-0.88
PromoterAI		0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs551803753; hg19: chr17-72744870;