chr5-141573996-TGGAGGAGGAGGAGGAGGAGGA-T

Variant names:

• chr5-141573996-TGGAGGAGGAGGAGGAGGAGGA-T
• rs3075570
• NM_005219.5:c.1833_1853delTCCTCCTCCTCCTCCTCCTCC

Variant summary

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

The NM_005219.5(DIAPH1):​c.1833_1853delTCCTCCTCCTCCTCCTCCTCC​(p.Pro612_Pro618del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000165 in 1,511,812 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.000016 (0 hom.)
• Consequence: DIAPH1 NM_005219.5 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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.1833_1853delTCCTCCTCCTCCTCCTCCTCC	p.Pro612_Pro618del	disruptive_inframe_deletion	Exon 16 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.1806_1826delTCCTCCTCCTCCTCCTCCTCC	p.Pro603_Pro609del	disruptive_inframe_deletion	Exon 15 of 27	NP_001073280.1	O60610-3
	DIAPH1	NM_001314007.2		c.1833_1853delTCCTCCTCCTCCTCCTCCTCC	p.Pro612_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.1833_1853delTCCTCCTCCTCCTCCTCCTCC	p.Pro612_Pro618del	disruptive_inframe_deletion	Exon 16 of 28	ENSP00000373706.4	O60610-1
	DIAPH1	ENST00000518047.5	TSL:5	c.1806_1826delTCCTCCTCCTCCTCCTCCTCC	p.Pro603_Pro609del	disruptive_inframe_deletion	Exon 15 of 27	ENSP00000428268.2	O60610-3
	DIAPH1	ENST00000647433.1		c.1833_1853delTCCTCCTCCTCCTCCTCCTCC	p.Pro612_Pro618del	disruptive_inframe_deletion	Exon 16 of 29	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes AF: 0.0000239 AC: 3 AN: 125478 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000513

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000159 AC: 22 AN: 1386334 Hom.: 0 AF XY: 0.0000161 AC XY: 11 AN XY: 683650

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

American (AMR) AF: 0.0000283 AC: 1 AN: 35304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 35360

South Asian (SAS) AF: 0.00 AC: 0 AN: 77860

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4444

European-Non Finnish (NFE) AF: 0.0000196 AC: 21 AN: 1072274

Other (OTH) AF: 0.00 AC: 0 AN: 57452

GnomAD4 genome AF: 0.0000239 AC: 3 AN: 125478 Hom.: 0 Cov.: 28 AF XY: 0.0000166 AC XY: 1 AN XY: 60152

African (AFR) AF: 0.00 AC: 0 AN: 32940

American (AMR) AF: 0.00 AC: 0 AN: 12422

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4354

South Asian (SAS) AF: 0.00 AC: 0 AN: 3778

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 226

European-Non Finnish (NFE) AF: 0.0000513 AC: 3 AN: 58434

Other (OTH) AF: 0.00 AC: 0 AN: 1678

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5
Mutation Taster		=130/70	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;