chr1-6424902-A-G

Variant names:

• chr1-6424902-A-G
• rs537986514
• NM_031475.3:c.-54A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_031475.3(ESPN):​c.-54A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000839 in 1,396,952 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: ESPN NM_031475.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.15
• Publications: 1 publications found

Genes affected

ESPN (HGNC:13281): (espin) This gene encodes a multifunctional actin-bundling protein. It plays a major role in regulating the organization, dimensions, dynamics, and signaling capacities of the actin filament-rich, microvillus-type specializations that mediate sensory transduction in various mechanosensory and chemosensory cells. Mutations in this gene are associated with autosomal recessive neurosensory deafness, and autosomal dominant sensorineural deafness without vestibular involvement. [provided by RefSeq, Nov 2009]

HES2 (HGNC:16005): (hes family bHLH transcription factor 2) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in anterior/posterior pattern specification; regulation of neurogenesis; and regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-6424902-A-G is Benign according to our data. Variant chr1-6424902-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1203363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00465 (705/151744) while in subpopulation AFR AF = 0.0163 (677/41502). AF 95% confidence interval is 0.0153. There are 5 homozygotes in GnomAd4. There are 338 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031475.3. 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
	ESPN	NM_031475.3	MANE Select	c.-54A>G		5_prime_UTR	Exon 1 of 13	NP_113663.2	B1AK53-1
	ESPN	NM_001367474.1		c.-54A>G		5_prime_UTR	Exon 1 of 15	NP_001354403.1
	ESPN	NM_001367473.1		c.-54A>G		5_prime_UTR	Exon 1 of 14	NP_001354402.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESPN	ENST00000645284.1	MANE Select	c.-54A>G		5_prime_UTR	Exon 1 of 13	ENSP00000496593.1	B1AK53-1
	ESPN	ENST00000636330.1	TSL:5	c.-54A>G		5_prime_UTR	Exon 1 of 11	ENSP00000490186.1	A0A1B0GUN9
	HES2	ENST00000377837.5	TSL:1	c.-448T>C		upstream_gene	N/A	ENSP00000367068.1	Q9Y543-2

Frequencies

GnomAD3 genomes AF: 0.00460 AC: 698 AN: 151636 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00336

GnomAD4 exome AF: 0.000375 AC: 467 AN: 1245208 Hom.: 0 Cov.: 29 AF XY: 0.000345 AC XY: 211 AN XY: 610824

African (AFR) AF: 0.0165 AC: 406 AN: 24662

American (AMR) AF: 0.000930 AC: 17 AN: 18280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20248

East Asian (EAS) AF: 0.00 AC: 0 AN: 25918

South Asian (SAS) AF: 0.00 AC: 0 AN: 63046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30948

Middle Eastern (MID) AF: 0.000568 AC: 2 AN: 3520

European-Non Finnish (NFE) AF: 0.00000694 AC: 7 AN: 1008088

Other (OTH) AF: 0.000693 AC: 35 AN: 50498

GnomAD4 genome AF: 0.00465 AC: 705 AN: 151744 Hom.: 5 Cov.: 33 AF XY: 0.00456 AC XY: 338 AN XY: 74192

African (AFR) AF: 0.0163 AC: 677 AN: 41502

American (AMR) AF: 0.00118 AC: 18 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67830

Other (OTH) AF: 0.00333 AC: 7 AN: 2104

Alfa AF: 0.00354 Hom.: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.65
PhyloP100		2.1
PromoterAI		-0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=296/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs537986514; hg19: chr1-6484962;