5-141573996-TGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGAGGAGGAGGAGGAGGAGGA

Variant names:

• chr5-141573996-T-TGGAGGA
• rs3075570
• NM_005219.5:c.1848_1853dupTCCTCC

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.1848_1853dupTCCTCC​(p.Pro617_Pro618dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0247 in 1,511,212 control chromosomes in the GnomAD database, including 190 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P618P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.024 (42 hom., cov: 28)
  • Exomes 𝑓: 0.025 (148 hom.)
• Consequence: DIAPH1 NM_005219.5 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• 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-T-TGGAGGA is Benign according to our data. Variant chr5-141573996-T-TGGAGGA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0239 (2998/125512) while in subpopulation EAS AF = 0.044 (191/4344). AF 95% confidence interval is 0.0389. There are 42 homozygotes in GnomAd4. There are 1440 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 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.1848_1853dupTCCTCC	p.Pro617_Pro618dup	disruptive_inframe_insertion	Exon 16 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.1821_1826dupTCCTCC	p.Pro608_Pro609dup	disruptive_inframe_insertion	Exon 15 of 27	NP_001073280.1	O60610-3
	DIAPH1	NM_001314007.2		c.1848_1853dupTCCTCC	p.Pro617_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.1848_1853dupTCCTCC	p.Pro617_Pro618dup	disruptive_inframe_insertion	Exon 16 of 28	ENSP00000373706.4	O60610-1
	DIAPH1	ENST00000518047.5	TSL:5	c.1821_1826dupTCCTCC	p.Pro608_Pro609dup	disruptive_inframe_insertion	Exon 15 of 27	ENSP00000428268.2	O60610-3
	DIAPH1	ENST00000647433.1		c.1848_1853dupTCCTCC	p.Pro617_Pro618dup	disruptive_inframe_insertion	Exon 16 of 29	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 2999 AN: 125442 Hom.: 42 Cov.: 28

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00990

Gnomad ASJ AF: 0.00682

Gnomad EAS AF: 0.0441

Gnomad SAS AF: 0.0278

Gnomad FIN AF: 0.0472

Gnomad MID AF: 0.0310

Gnomad NFE AF: 0.0298

Gnomad OTH AF: 0.0131

GnomAD2 exomes AF: 0.0287 AC: 2409 AN: 83800 AF XY: 0.0290

Gnomad AFR exome AF: 0.0167

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.00546

Gnomad EAS exome AF: 0.0811

Gnomad FIN exome AF: 0.0348

Gnomad NFE exome AF: 0.0289

Gnomad OTH exome AF: 0.0288

GnomAD4 exome AF: 0.0248 AC: 34385 AN: 1385700 Hom.: 148 Cov.: 35 AF XY: 0.0246 AC XY: 16823 AN XY: 683356

African (AFR) AF: 0.0133 AC: 417 AN: 31384

American (AMR) AF: 0.00737 AC: 260 AN: 35302

Ashkenazi Jewish (ASJ) AF: 0.00505 AC: 125 AN: 24732

East Asian (EAS) AF: 0.0442 AC: 1562 AN: 35350

South Asian (SAS) AF: 0.0218 AC: 1697 AN: 77824

European-Finnish (FIN) AF: 0.0419 AC: 1988 AN: 47426

Middle Eastern (MID) AF: 0.00788 AC: 35 AN: 4444

European-Non Finnish (NFE) AF: 0.0252 AC: 27017 AN: 1071796

Other (OTH) AF: 0.0224 AC: 1284 AN: 57442

GnomAD4 genome AF: 0.0239 AC: 2998 AN: 125512 Hom.: 42 Cov.: 28 AF XY: 0.0239 AC XY: 1440 AN XY: 60210

African (AFR) AF: 0.0122 AC: 404 AN: 33032

American (AMR) AF: 0.00989 AC: 123 AN: 12434

Ashkenazi Jewish (ASJ) AF: 0.00682 AC: 21 AN: 3078

East Asian (EAS) AF: 0.0440 AC: 191 AN: 4344

South Asian (SAS) AF: 0.0274 AC: 103 AN: 3762

European-Finnish (FIN) AF: 0.0472 AC: 366 AN: 7754

Middle Eastern (MID) AF: 0.0240 AC: 5 AN: 208

European-Non Finnish (NFE) AF: 0.0298 AC: 1741 AN: 58406

Other (OTH) AF: 0.0130 AC: 22 AN: 1692

Alfa AF: 0.0118 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	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; COSMIC: COSV108062297; COSMIC: COSV108062297;