5-141573996-TGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGAGGAGGAGGA

Variant names:

• chr5-141573996-TGGA-T
• rs3075570
• NM_005219.5:c.1851_1853delTCC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_005219.5(DIAPH1):​c.1851_1853delTCC​(p.Pro618del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0319 in 1,280,532 control chromosomes in the GnomAD database, including 187 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (29 hom., cov: 28)
  • Exomes 𝑓: 0.033 (158 hom.)
• Consequence: DIAPH1 NM_005219.5 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.13
• Publications: 2 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: Orphanet, ClinGen
• progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant nonsyndromic hearing loss 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005219.5
• BP6: Variant 5-141573996-TGGA-T is Benign according to our data. Variant chr5-141573996-TGGA-T is described in ClinVar as Benign. ClinVar VariationId is 226563.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 = 0.0225 (2819/125344) while in subpopulation AFR AF = 0.0271 (893/32990). AF 95% confidence interval is 0.0256. There are 29 homozygotes in GnomAd4. There are 1298 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 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.1851_1853delTCC	p.Pro618del	disruptive_inframe_deletion	Exon 16 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.1824_1826delTCC	p.Pro609del	disruptive_inframe_deletion	Exon 15 of 27	NP_001073280.1	O60610-3
	DIAPH1	NM_001314007.2		c.1851_1853delTCC	p.Pro618del	disruptive_inframe_deletion	Exon 16 of 29	NP_001300936.1	A0A2R8Y5N1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	ENST00000389054.8	TSL:5 MANE Select	c.1851_1853delTCC	p.Pro618del	disruptive_inframe_deletion	Exon 16 of 28	ENSP00000373706.4	O60610-1
	DIAPH1	ENST00000518047.5	TSL:5	c.1824_1826delTCC	p.Pro609del	disruptive_inframe_deletion	Exon 15 of 27	ENSP00000428268.2	O60610-3
	DIAPH1	ENST00000647433.1		c.1851_1853delTCC	p.Pro618del	disruptive_inframe_deletion	Exon 16 of 29	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 2813 AN: 125282 Hom.: 29 Cov.: 28

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.000920

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.00351

Gnomad MID AF: 0.0398

Gnomad NFE AF: 0.0237

Gnomad OTH AF: 0.0197

GnomAD2 exomes AF: 0.0722 AC: 6050 AN: 83800 AF XY: 0.0801

Gnomad AFR exome AF: 0.0450

Gnomad AMR exome AF: 0.0327

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.00828

Gnomad FIN exome AF: 0.0753

Gnomad NFE exome AF: 0.0829

Gnomad OTH exome AF: 0.0628

GnomAD4 exome AF: 0.0329 AC: 38061 AN: 1155188 Hom.: 158 AF XY: 0.0340 AC XY: 18958 AN XY: 557948

African (AFR) AF: 0.0355 AC: 915 AN: 25796

American (AMR) AF: 0.0279 AC: 607 AN: 21772

Ashkenazi Jewish (ASJ) AF: 0.0857 AC: 1585 AN: 18500

East Asian (EAS) AF: 0.00925 AC: 225 AN: 24330

South Asian (SAS) AF: 0.0401 AC: 1952 AN: 48668

European-Finnish (FIN) AF: 0.0273 AC: 949 AN: 34790

Middle Eastern (MID) AF: 0.0464 AC: 165 AN: 3554

European-Non Finnish (NFE) AF: 0.0323 AC: 30082 AN: 932056

Other (OTH) AF: 0.0346 AC: 1581 AN: 45722

GnomAD4 genome AF: 0.0225 AC: 2819 AN: 125344 Hom.: 29 Cov.: 28 AF XY: 0.0216 AC XY: 1298 AN XY: 60108

African (AFR) AF: 0.0271 AC: 893 AN: 32990

American (AMR) AF: 0.0171 AC: 213 AN: 12422

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 150 AN: 3078

East Asian (EAS) AF: 0.000923 AC: 4 AN: 4334

South Asian (SAS) AF: 0.0109 AC: 41 AN: 3766

European-Finnish (FIN) AF: 0.00351 AC: 27 AN: 7698

Middle Eastern (MID) AF: 0.0385 AC: 8 AN: 208

European-Non Finnish (NFE) AF: 0.0237 AC: 1384 AN: 58356

Other (OTH) AF: 0.0190 AC: 32 AN: 1688

Alfa AF: 0.0737 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Autosomal dominant nonsyndromic hearing loss 1 (2)
-	-	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
PhyloP100		2.1
Mutation Taster		=76/24	polymorphism

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: rs3075570; hg19: chr5-140953563; COSMIC: COSV53882307; COSMIC: COSV53882307;