5-141573996-TGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA

Variant names:

• chr5-141573996-T-TGGAGGAGGAGGAGGAGGA
• rs3075570
• NM_005219.5:c.1836_1853dupTCCTCCTCCTCCTCCTCC

Variant summary

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

The NM_005219.5(DIAPH1):​c.1836_1853dupTCCTCCTCCTCCTCCTCC​(p.Pro613_Pro618dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_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 (★). Synonymous variant affecting the same amino acid position (i.e. P618P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.000039 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DIAPH1 NM_005219.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: 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.1836_1853dupTCCTCCTCCTCCTCCTCC	p.Pro613_Pro618dup	disruptive_inframe_insertion	Exon 16 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.1809_1826dupTCCTCCTCCTCCTCCTCC	p.Pro604_Pro609dup	disruptive_inframe_insertion	Exon 15 of 27	NP_001073280.1	O60610-3
	DIAPH1	NM_001314007.2		c.1836_1853dupTCCTCCTCCTCCTCCTCC	p.Pro613_Pro618dup	disruptive_inframe_insertion	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.1836_1853dupTCCTCCTCCTCCTCCTCC	p.Pro613_Pro618dup	disruptive_inframe_insertion	Exon 16 of 28	ENSP00000373706.4	O60610-1
	DIAPH1	ENST00000518047.5	TSL:5	c.1809_1826dupTCCTCCTCCTCCTCCTCC	p.Pro604_Pro609dup	disruptive_inframe_insertion	Exon 15 of 27	ENSP00000428268.2	O60610-3
	DIAPH1	ENST00000647433.1		c.1836_1853dupTCCTCCTCCTCCTCCTCC	p.Pro613_Pro618dup	disruptive_inframe_insertion	Exon 16 of 29	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000390 AC: 54 AN: 1386304 Hom.: 0 Cov.: 35 AF XY: 0.0000424 AC XY: 29 AN XY: 683634

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31386

American (AMR) AF: 0.0000850 AC: 3 AN: 35300

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: 0.0000457 AC: 49 AN: 1072250

Other (OTH) AF: 0.0000348 AC: 2 AN: 57452

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

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		2.1
Mutation Taster		=77/23	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;