rs2074913

Variant names:

• chr5-141618784-G-A
• rs2074913
• NM_005219.5:c.117+14C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_005219.5(DIAPH1):​c.117+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.068 in 1,532,352 control chromosomes in the GnomAD database, including 4,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (359 hom., cov: 32)
  • Exomes 𝑓: 0.069 (3738 hom.)
• Consequence: DIAPH1 NM_005219.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.88
• Publications: 7 publications found

Genes affected

DIAPH1 (HGNC:2876): (diaphanous related formin 1) This gene is a homolog of the Drosophila diaphanous gene, and has been linked to autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive low-frequency hearing loss. Actin polymerization involves proteins known to interact with diaphanous protein in Drosophila and mouse. It has therefore been speculated that this gene may have a role in the regulation of actin polymerization in hair cells of the inner ear. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

DIAPH1 Gene-Disease associations (from GenCC):

• DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autosomal dominant nonsyndromic hearing loss 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000228737 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 5-141618784-G-A is Benign according to our data. Variant chr5-141618784-G-A is described in ClinVar as Benign. ClinVar VariationId is 45212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0773 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005219.5. 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
	DIAPH1	NM_005219.5	MANE Select	c.117+14C>T		intron	N/A	NP_005210.3
	DIAPH1	NM_001079812.3		c.117+14C>T		intron	N/A	NP_001073280.1
	DIAPH1	NM_001314007.2		c.117+14C>T		intron	N/A	NP_001300936.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	ENST00000389054.8	TSL:5 MANE Select	c.117+14C>T		intron	N/A	ENSP00000373706.4
	DIAPH1	ENST00000518047.5	TSL:5	c.117+14C>T		intron	N/A	ENSP00000428268.2
	DIAPH1	ENST00000647433.1		c.117+14C>T		intron	N/A	ENSP00000494675.1

Frequencies

GnomAD3 genomes AF: 0.0576 AC: 8764 AN: 152134 Hom.: 361 Cov.: 32

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0366

Gnomad ASJ AF: 0.0907

Gnomad EAS AF: 0.0432

Gnomad SAS AF: 0.0500

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0791

Gnomad OTH AF: 0.0755

GnomAD2 exomes AF: 0.0627 AC: 10183 AN: 162482 AF XY: 0.0624

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.0291

Gnomad ASJ exome AF: 0.0834

Gnomad EAS exome AF: 0.0407

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.0721

Gnomad OTH exome AF: 0.0647

GnomAD4 exome AF: 0.0691 AC: 95427 AN: 1380102 Hom.: 3738 Cov.: 25 AF XY: 0.0691 AC XY: 47246 AN XY: 683928

African (AFR) AF: 0.0112 AC: 346 AN: 30906

American (AMR) AF: 0.0317 AC: 1178 AN: 37142

Ashkenazi Jewish (ASJ) AF: 0.0824 AC: 2048 AN: 24854

East Asian (EAS) AF: 0.0271 AC: 972 AN: 35810

South Asian (SAS) AF: 0.0515 AC: 4046 AN: 78586

European-Finnish (FIN) AF: 0.121 AC: 6010 AN: 49648

Middle Eastern (MID) AF: 0.0764 AC: 423 AN: 5538

European-Non Finnish (NFE) AF: 0.0722 AC: 76521 AN: 1060302

Other (OTH) AF: 0.0677 AC: 3883 AN: 57316

GnomAD4 genome AF: 0.0576 AC: 8767 AN: 152250 Hom.: 359 Cov.: 32 AF XY: 0.0588 AC XY: 4377 AN XY: 74442

African (AFR) AF: 0.0126 AC: 524 AN: 41564

American (AMR) AF: 0.0366 AC: 560 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0907 AC: 315 AN: 3472

East Asian (EAS) AF: 0.0436 AC: 225 AN: 5166

South Asian (SAS) AF: 0.0499 AC: 241 AN: 4834

European-Finnish (FIN) AF: 0.124 AC: 1321 AN: 10614

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0791 AC: 5376 AN: 67978

Other (OTH) AF: 0.0776 AC: 164 AN: 2114

Alfa AF: 0.0710 Hom.: 125

Bravo AF: 0.0477

Asia WGS AF: 0.0860 AC: 297 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 1 (1)
-	-	1	Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Benign	0.88
PhyloP100		1.9
PromoterAI		-0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2074913; hg19: chr5-140998351;