5-141573996-TGGAGGAGGAGGAGGAGGAGGA-TGGAGGA

Variant names:

• chr5-141573996-TGGAGGAGGAGGAGGA-T
• rs3075570
• NM_005219.5:c.1839_1853delTCCTCCTCCTCCTCC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_005219.5(DIAPH1):​c.1839_1853delTCCTCCTCCTCCTCC​(p.Pro614_Pro618del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000284 in 1,511,878 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000024 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000029 (1 hom.)
• Consequence: DIAPH1 NM_005219.5 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.53
• 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: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005219.5

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.1839_1853delTCCTCCTCCTCCTCC	p.Pro614_Pro618del	disruptive_inframe_deletion	Exon 16 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.1812_1826delTCCTCCTCCTCCTCC	p.Pro605_Pro609del	disruptive_inframe_deletion	Exon 15 of 27	NP_001073280.1	O60610-3
	DIAPH1	NM_001314007.2		c.1839_1853delTCCTCCTCCTCCTCC	p.Pro614_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.1839_1853delTCCTCCTCCTCCTCC	p.Pro614_Pro618del	disruptive_inframe_deletion	Exon 16 of 28	ENSP00000373706.4	O60610-1
	DIAPH1	ENST00000518047.5	TSL:5	c.1812_1826delTCCTCCTCCTCCTCC	p.Pro605_Pro609del	disruptive_inframe_deletion	Exon 15 of 27	ENSP00000428268.2	O60610-3
	DIAPH1	ENST00000647433.1		c.1839_1853delTCCTCCTCCTCCTCC	p.Pro614_Pro618del	disruptive_inframe_deletion	Exon 16 of 29	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes AF: 0.0000239 AC: 3 AN: 125476 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000529

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000171

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000289 AC: 40 AN: 1386332 Hom.: 1 AF XY: 0.0000366 AC XY: 25 AN XY: 683648

African (AFR) AF: 0.00 AC: 0 AN: 31388

American (AMR) AF: 0.00 AC: 0 AN: 35304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24734

East Asian (EAS) AF: 0.0000566 AC: 2 AN: 35360

South Asian (SAS) AF: 0.000283 AC: 22 AN: 77860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4442

European-Non Finnish (NFE) AF: 0.0000121 AC: 13 AN: 1072274

Other (OTH) AF: 0.0000522 AC: 3 AN: 57452

GnomAD4 genome AF: 0.0000239 AC: 3 AN: 125546 Hom.: 0 Cov.: 28 AF XY: 0.0000332 AC XY: 2 AN XY: 60228

African (AFR) AF: 0.00 AC: 0 AN: 33032

American (AMR) AF: 0.00 AC: 0 AN: 12438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3078

East Asian (EAS) AF: 0.00 AC: 0 AN: 4344

South Asian (SAS) AF: 0.000531 AC: 2 AN: 3766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 208

European-Non Finnish (NFE) AF: 0.0000171 AC: 1 AN: 58420

Other (OTH) AF: 0.00 AC: 0 AN: 1692

Alfa AF: 0.00 Hom.: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	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		4.5
Mutation Taster		=165/35	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3075570; hg19: chr5-140953563;