17-74748854-C-G

Variant names:

• chr17-74748854-C-G
• rs769816246
• NM_004252.5:c.8C>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004252.5(NHERF1):​c.8C>G​(p.Ala3Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000902 in 1,440,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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: 32)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: NHERF1 NM_004252.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.067008585).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHERF1	NM_004252.5	c.8C>G	p.Ala3Gly	missense_variant	Exon 1 of 6	ENST00000262613.10	NP_004243.1
SLC9A3R1-AS1	NR_187307.1	n.879G>C		non_coding_transcript_exon_variant	Exon 2 of 3
MIR3615	NR_037409.1	n.*155C>G		downstream_gene_variant
MIR3615	unassigned_transcript_3091	n.*171C>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHERF1	ENST00000262613.10	c.8C>G	p.Ala3Gly	missense_variant	Exon 1 of 6	1	NM_004252.5	ENSP00000262613.5
NHERF1	ENST00000583369.5	c.8C>G	p.Ala3Gly	missense_variant	Exon 1 of 3	3		ENSP00000464321.1
SLC9A3R1-AS1	ENST00000585285.1	n.59G>C		non_coding_transcript_exon_variant	Exon 1 of 2	3
MIR3615	ENST00000581999.1	n.*155C>G		downstream_gene_variant		6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000425 AC: 9 AN: 211734 Hom.: 0 AF XY: 0.0000338 AC XY: 4 AN XY: 118262

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000271

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000902 AC: 13 AN: 1440476 Hom.: 0 Cov.: 31 AF XY: 0.00000838 AC XY: 6 AN XY: 716218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000205

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000339 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.015	T;T
Eigen	Benign	-0.0028
Eigen_PC	Benign	0.087
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	.;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.15	.;N
REVEL	Benign	0.036
Sift	Benign	0.032	.;D
Sift4G	Uncertain	0.047	D;T
Polyphen		0.73	.;P
Vest4		0.29
MutPred		0.28		Loss of stability (P = 0.0745);Loss of stability (P = 0.0745);
MVP		0.63
MPC		1.1
ClinPred		0.20	T
GERP RS		4.3
Varity_R		0.095
gMVP		0.37

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: rs769816246; hg19: chr17-72744993;