5-141573626-G-C

Variant names:

• chr5-141573626-G-C
• rs199749212
• NM_005219.5:c.2224C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005219.5(DIAPH1):​c.2224C>G​(p.Pro742Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000488 in 1,613,728 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00034 (1 hom., cov: 28)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 7.09
• Publications: 1 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: ClinGen, Orphanet
• autosomal dominant nonsyndromic hearing loss 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24226448).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	NM_005219.5	MANE Select	c.2224C>G	p.Pro742Ala	missense	Exon 16 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.2197C>G	p.Pro733Ala	missense	Exon 15 of 27	NP_001073280.1
	DIAPH1	NM_001314007.2		c.2224C>G	p.Pro742Ala	missense	Exon 16 of 29	NP_001300936.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	ENST00000389054.8	TSL:5 MANE Select	c.2224C>G	p.Pro742Ala	missense	Exon 16 of 28	ENSP00000373706.4
	DIAPH1	ENST00000518047.5	TSL:5	c.2197C>G	p.Pro733Ala	missense	Exon 15 of 27	ENSP00000428268.2
	DIAPH1	ENST00000647433.1		c.2224C>G	p.Pro742Ala	missense	Exon 16 of 29	ENSP00000494675.1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 151902 Hom.: 1 Cov.: 28

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000257 AC: 64 AN: 249034 AF XY: 0.000178

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000514

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000503 AC: 736 AN: 1461826 Hom.: 0 Cov.: 39 AF XY: 0.000465 AC XY: 338 AN XY: 727204

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.000157 AC: 7 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000636 AC: 707 AN: 1111978

Other (OTH) AF: 0.000315 AC: 19 AN: 60388

GnomAD4 genome AF: 0.000342 AC: 52 AN: 151902 Hom.: 1 Cov.: 28 AF XY: 0.000270 AC XY: 20 AN XY: 74190

African (AFR) AF: 0.000194 AC: 8 AN: 41342

American (AMR) AF: 0.000131 AC: 2 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000424 Hom.: 0

Bravo AF: 0.000325

ESP6500AA AF: 0.000266 AC: 1

ESP6500EA AF: 0.000487 AC: 4

ExAC AF: 0.000215 AC: 26

EpiCase AF: 0.000709

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (2)
-	1	-	Autosomal dominant nonsyndromic hearing loss 1 (1)
-	1	-	DIAPH1-related disorder (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.49
Sift	Benign	0.94	T
Sift4G	Benign	0.065	T
Polyphen		0.83	P
Vest4		0.29
MVP		0.94
MPC		0.11
ClinPred		0.11	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.065
gMVP		0.20
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199749212; hg19: chr5-140953193; COSMIC: COSV99527529; COSMIC: COSV99527529;