rs2302102

Variant names:

• chr5-141524225-G-A
• rs2302102
• NM_005219.5:c.3579C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-141524225-G-A
• chr5-141524225-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005219.5(DIAPH1):​c.3579C>T​(p.Gly1193Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,613,320 control chromosomes in the GnomAD database, including 719 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (52 hom., cov: 31)
  • Exomes 𝑓: 0.026 (667 hom.)
• Consequence: DIAPH1 NM_005219.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.21
• Publications: 10 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 5-141524225-G-A is Benign according to our data. Variant chr5-141524225-G-A is described in ClinVar as Benign. ClinVar VariationId is 45215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.023 (3504/152128) while in subpopulation EAS AF = 0.0464 (240/5168). AF 95% confidence interval is 0.0416. There are 52 homozygotes in GnomAd4. There are 1785 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 52 AD,AR gene

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.3579C>T	p.Gly1193Gly	synonymous	Exon 27 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.3552C>T	p.Gly1184Gly	synonymous	Exon 26 of 27	NP_001073280.1
	DIAPH1	NM_001314007.2		c.3579C>T	p.Gly1193Gly	synonymous	Exon 27 of 29	NP_001300936.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	ENST00000389054.8	TSL:5 MANE Select	c.3579C>T	p.Gly1193Gly	synonymous	Exon 27 of 28	ENSP00000373706.4
	DIAPH1	ENST00000518047.5	TSL:5	c.3552C>T	p.Gly1184Gly	synonymous	Exon 26 of 27	ENSP00000428268.2
	DIAPH1	ENST00000647433.1		c.3579C>T	p.Gly1193Gly	synonymous	Exon 27 of 29	ENSP00000494675.1

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3503 AN: 152010 Hom.: 52 Cov.: 31

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.00963

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0465

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.0509

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0278

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.0254 AC: 6333 AN: 249380 AF XY: 0.0259

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.00684

Gnomad ASJ exome AF: 0.00507

Gnomad EAS exome AF: 0.0446

Gnomad FIN exome AF: 0.0506

Gnomad NFE exome AF: 0.0271

Gnomad OTH exome AF: 0.0224

GnomAD4 exome AF: 0.0263 AC: 38359 AN: 1461192 Hom.: 667 Cov.: 30 AF XY: 0.0262 AC XY: 19034 AN XY: 726928

African (AFR) AF: 0.0124 AC: 415 AN: 33472

American (AMR) AF: 0.00698 AC: 312 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00559 AC: 146 AN: 26134

East Asian (EAS) AF: 0.0456 AC: 1811 AN: 39690

South Asian (SAS) AF: 0.0242 AC: 2091 AN: 86242

European-Finnish (FIN) AF: 0.0510 AC: 2725 AN: 53412

Middle Eastern (MID) AF: 0.00815 AC: 47 AN: 5768

European-Non Finnish (NFE) AF: 0.0264 AC: 29385 AN: 1111364

Other (OTH) AF: 0.0236 AC: 1427 AN: 60388

GnomAD4 genome AF: 0.0230 AC: 3504 AN: 152128 Hom.: 52 Cov.: 31 AF XY: 0.0240 AC XY: 1785 AN XY: 74380

African (AFR) AF: 0.0114 AC: 472 AN: 41490

American (AMR) AF: 0.00962 AC: 147 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.0464 AC: 240 AN: 5168

South Asian (SAS) AF: 0.0288 AC: 139 AN: 4824

European-Finnish (FIN) AF: 0.0509 AC: 538 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0278 AC: 1890 AN: 68004

Other (OTH) AF: 0.0142 AC: 30 AN: 2110

Alfa AF: 0.0255 Hom.: 164

Bravo AF: 0.0192

Asia WGS AF: 0.0480 AC: 166 AN: 3478

EpiCase AF: 0.0222

EpiControl AF: 0.0232

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	-0.72
CADD	Benign	2.7
DANN	Benign	0.58
PhyloP100		-2.2
PromoterAI		-0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs2302102; hg19: chr5-140903792; COSMIC: COSV53880169; COSMIC: COSV53880169;